THE  LIBRARY 

OF 

THE  UNIVERSITY 

OF  CALIFORNIA 

LOS  ANGELES 


GIFT  OF 
Dr.  Emil  Bogen 


:^ 


CLINICAL  PATHOLOGY 


PROPERTY  OF 

WAITER  §.  ItoUNT.  M.  fl. 


APR      tso: 


OF 


THE     BLOOD 


A  TREATISE  ON  THE  GENERAL  PRINCIPLES  AND  SPECIAL 
APPLICATIONS  OF  HEMATOLOGY 


BY 


JAMES   EWING,    A.M.,  M.D. 

Professor  of  Pathology  in  Cornell  University  JIedical  College,  New  York  City. 


ILLUSTRATED  WITH  THIRTY  ENGRAVINGS,  AND  FOURTEEN  COLORED 
PLATES    DRAWN    BY    THE    AUTHOR 


LEA     BROTHERS     &    CO. 
PHILADELPHIA     AND     NEW     YORK 


Entered  according  to  the  Act  of  Congress  in  the  year  1901,  by 

LEA  BROTHERS  &  CO. 
In  the  Office  of  the  Librarian  of  Congress.     All  rights  reserved. 


iiemedical 
Ubsarj 

100 


TO 

PROFESSOR  T.    MITCHELL   PRUDDEN,    M.D.,    LL.D., 

IN   APPRECIATION  OF  HIS   CONSTANT  AID, 
FEEELY  EENDERED  TO 

THE  AUTHOR 

DURING  A  TERM  OF  SERVICE  IN  THE  LABORATORY  OF   THE 
NEW   YORK   COLLEGE  OF  PHYSICIANS  AND  SURGEONS, 

THIS  WORK   IS 

'GRATEFULLY   DEDICATED. 


f^f^'lH^ 


PREFACE. 


The  rapid  advances  in  the  knowledge  of  the  pathology  of  the  blood 
and  the  multitudinous  applications  of  this  knowledge  in  clinical  diag- 
nosis which  the  last  decade  has  witnessed  have  brought  forth  several 
critical  treatises  on  hematology,  and  still  furnish,  as  the  writer  believes, 
abundant  reason  for  the  preparation  of  another  such  work,  in  English. 

Although  the  clinical  bearings  of  the  subject  have  been  partly  or 
fully  accessible  to  English  readers  in  some  recent  text-books,  many 
later  contributions  to  the  pathology  of  the  blood  and  blood-forming 
organs  have  had  to  be  sought  elsewhere,  often  in  the  original  articles. 
This  omission  the  present  work  endeavors  to  supply. 

Much  of  the  theoretical  discussion  in  the  volume,  abstracts  of  special 
articles,  and  reports  of  cases,  have  been  set  in  fine  print,  so  as  not  to 
encumber  the  main  text,  which  has  been  constructed  for  the  student 
and  general  reader.  The  wants  of  the  laboratory  worker  and  special 
student  of  hematology  have  been  partly  considered  in  the  chapter  on 
Technics  and  Chemistry,  and  in  the  limited  references  to  pathological 
anatomy. 

There  are  probably  always  some  deficiencies  in  a  treatise  closely  re- 
lating to  clinical  medicine  when  that  treatise  emanates  from  a  patho- 
logical laboratory.  Yet  a  comparison  of  the  various  extant  works  on 
the  so-called  "  clinical "  pathology  of  the  blood  has  convinced  the 
writer  that  clinical  pathology  is  pathology  still,  and  that  a  wide  experi- 
ence at  the  autopsy  table  and  in  the  microscopical  examination  of  dis- 
eased tissues  furnishes  an  absolutely  essential  standpoint  from  which 
to  view  pathological  changes  in  the  blood.  The  present  volume  aims 
therefore  to  associate  changes  in  the  blood  as  closely  as  possible  with 
lesions  in  the  viscera,  without  which  combination  the  former  are  very 
often  unintelligible. 


Vi  PREFACE. 

In  the  preparation  of  the  work  all  available  sources  of  information 
have  been  freely  consulted,  and  the  writer  has  profited  especially  by 
the  labors  of  Ehrlich,  Limbeck,  Hayem,  Lukjanow,  Lowit,  Grawitz, 
Stengel,  Cabot,  and  many  others.  An  endeavor  has  been  made  to 
discriminate  between  authorities,  and  in  all  details  of  important  sub- 
jects the  author  has  invariably  consulted  the  original  sources  of  in- 
formation. Works  without  bibliography  have  been  of  little  value  in 
this  task,  and  the  considerable  number  of  references  involved  have 
therefore  been  included  as  a  feature  of  the  present  volume. 

J.  E. 


CONTENTS. 

INTRODUCTORY. 

ON    THE    INTERPRETATION    OF    ANALYSES    OF    THE    BLOOD. 

PART   I. 

GENERAL    PHYSIOLOGY    AND    PATHOLOGY. 

CHAPTER  I. 

TECHNICS. 

Qualitative  tests  for  blood 23 

Volume  of  red  cells  and  plasma 26 

Euumeration  of  blood  cells 30 

Hemoglobin,  iron 38 

Histological  examination  of  blood 46 

Specific  gravity 49 

Alkalescence 51 

Osmotic  tension 53 

Glycogen,  Fat 55 

Bibliograpby 56 

CHAPTER  II. 

CHEMISTRY    OF    THE   BLOOD. 

Red  cells,  Leucocytes 59 

Serum 62 

The  Whole  Blood .' 64 

The  Blood-ash 66 

Urea,  Uric  Acid,  Glucose,  Glycogen 68 

Acetonemia,  Lipacidemia,  Cholemia 71 

Specific  gravity 73 

Osmotic  tension 75 

Alkalescence,  Basic  Capacity 77 

Bibliography 79 

CHAPTER  III. 

MORPHOLOGY   AND    PHYSIOLOGY   OF    RED    CELLS. 

Structure  and  staining  reactions 82 

Degenerative  changes 85 

Numbers,  Polycythemia,  Oligocythemia 89 

Bibliography  103 


viii  CONTENTS. 

CHAPTER  IV. 

THE   LEUCOCYTES   AND   LEUCOCYTOSIS. 

Morphology 106 

Numbers  and  proportions 110 

Degenerative  changes 112 

Leucocy tosis,  classification 115 

Relation  to  phagocytosis  and  immunity 119 

Clinical  types  of  Leucocytosis 122 

Experimental  Leucocytosis 131 

Bibliography 134 

Eosinophilia 137 

Lymphocytosis 148 

Bibliography 148 

CHAPTER  V. 

DEVELOPMENT    OF   BLOOD    CELLS. 

Erythrocytes ._ 149 

Leucocytes 154 

Blood  plates 159 

Bibliography 160 


PART   II. 

SPECIAL    PATHOLOGY    OF    THE    BLOOD. 

CHAPTER  VI. 

CHLOROSIS. 

Etiologj' 168 

Changes  in  the  Blood 165 

Regeneration  of  Blood 168 

Varieties  of  Chlorosis,  Pseudo- chlorosis 169 

Bibliography 171 

CHAPTER  VII. 

PROGRESSIVE  PERNICIOUS  ANEMIA, 

Historical 172 

Etiology ;^74 

Pathological  changes  in  Viscera 183 

Pathogenesis i  og 

Changes  in  the  Blood Igy 

Resume ^qo 

Bibliography '-^gg 


CONTENTS.  IX 

CHAPTER  VIII. 

LEUKEMIA. 

Historical 198 

Etiology 201 

Pathological  changes  in  Viscera 204 

Pathogenesis 208 

Changes  in  the  Blood 210 

Diagnosis  of  Leukemia 219 

Bibliography 220 

CHAPTER   IX. 

PSEUDO-LEUKEMIA. 

Historical 223 

Anatomical  characters 224 

Relation  to  Leukemia,  Pernicious  Anemia,  Tuberculosis  226 

Changes  in  the  Blood 229 

Bibliography  231 

CHAPTER  X. 

ANEMIA    INFANTUM    PSEUDO-LEUKEMICA,     SPLENECTOMY. 

Historical 233 

Etiology  233 

Pathological  changes  in  Viscera 234 

Changes  in  the  Blood .^ 234 

Significance  of  v.  Jaksch's  anemia 235 

Bibliography 237 

Splenectomy. 

Effects  of  Splenectomy  in  Animals 238 

Splenectomy  in  Man 239 

Bibliography 241 


PART   III. 

THE    ACUTE    INFECTIOUS    DISEASES. 

INTRODUCTORY    SECTION. 

THE   BLOOD    IN    FEVER. 

Chemical  changes.  Resistance  of  red  cells 243 

Febrile  Hydremia 244 

Action  of  Bacteria  upon  the  Blood 245 

Bibliography 246 


X  CONTENTS. 

CHAPTER   XI. 

PNEUMONIA.       DIPHTHERIA. 

Pneumonia. 

Gross  changes,  Red  cells,  Leucocytes 248 

Bacteriology ^^'^ 

Diphtheria. 

Red  cells,  Leucocytes 255 

Effects  of  Antitoxine 257 


CHAPTER  XII. 

EXANTHEMATA. 

Variola 259 

Vaccinia 260 

Varicella 260 

Scarlatina 261 

Measles 262 


CHAPTER  XIII. 

TYPHOID    FEVER. 

Red  cells.  Leucocytes 264 

Bacteriology 267 

Bibliography,  on  Pneumonia,  Diphtheria,  Exanthems,  and  Typhoid  Fever  268 


CHAPTER  XIV. 

WIDAl's    TEST. 

The  reaction,  etc. , 271 

Bibliography 278 

CHAPTER  XV. 

MISCELLANEOUS   INFECTIOUS   DISEASES. 

Septicemia,  Pyemia,  Osteomyelitis 280 

Appendicitis,  Abscess,  Erysipelas 283 

Acute  Rheumatism,  Tonsillitis,  Whooping-cough 285 

Inflammations  of  Serous  Membranes 287 

Gonorrhea,  Yellow  Fever 288 

Typhus  Fever,  Influenza 289 

Tetanus,  Plague,  Malta  Fever 290 

Actinomycosis,  Glanders,  Anthrax 291 

Bibliography  291 


k 


CONTENTS.  XI 

CHAPTER  XVI. 

SYPHILIS,    TUBERCULOSIS,    LEPROSY. 

Syphilis,  Grades  of  Anemia 293 

Effects  of  Mercury 294 

Congenital  Syphilis 297 

Tuberculosis,  Grades  of  Anemia 298 

Tuberculosis  of  Meninges,  Bones  and  Joints 302 

Chemistry,  Bacteriology 303 

Leprosy 304 

Bibliography  305 


PART   IV. 

CONSTITUTIONAL    DISEASES. 

CHAPTER   XVII. 

HEMORRHAGIC    DISEASES    AND    DIATHESIS. 

Purpura  Hemorrhagica 307 

Hemophilia 310 

Scurvy 311 

Hemocytolysis 314 

Methemoglobinemia 316 

Paroxysmal  Hemoglobinuria 317 

Bibliography  320 

CHAPTER   XVIII. 

MISCELLANEOUS    CONSTITUTIONAL    DISEASES. 

Diabetes  322 

Obesity  324 

Addison' s  Disease 325 

Osteomalacia  327 

Kachitis 328 

Myxedema  330 

Bibliography  331 

CHAPTER   XIX. 

NERVOUS    AND    MENTAL    DISEASES. 

Mania,  General  Paresis,  Epilepsy,   etc 333 

Beri-beri 335 

Chorea,  Graves'  Disease 336 

Bibliography 336 


xii  CONTENTS. 

PART   V. 

GENERAL   DISEASES    OF   VISCERA. 

CHAPTER   XX. 

THE    HEMOPOIETIC    SYSTEM. 

Liver,  general  considerations,  special  diseases 337 

Esophagus 342 

Stomach,  general  considerations,  special  diseases 343 

Intestines,  absorption  and  depletion,  special  disease? 349 

Bibliography 352 


CHAPTER   XXI. 

LUNGS,    HEART,     KIDNEYS. 

Diseases  of  Lungs,  Asphyxia 354 

Diseases  of  Heart,  Malignant  Endocarditis 357 

Diseases  of  Kidneys,  Uremia 361 

Bibliography  366 


CHAPTER   XXII. 

MALIGNANT    TUMORS. 

Carcinoma 368 

Sarcoma 373 

Bibliography 375 


PAET  VI. 

ANIMAL    PARASITES. 

CHAPTER   XXIII. 

MALARIA. 

Technics 077 

Morphology  of  Parasites 381 

Plurality  of  species  in  Estivo-autumnal  group  392 

Crescents,  Flagellate  Bodies 396 

Development  in  Mosquito 399 

Conjugation '^^^^'^^^^^^^''mO 

Occurrence  of  Parasites  in  the  Blood .401 

Malarial  Anemia AQ'i 

Leucocytes  in  Malaria ^q^ 

Bibliography ^^'^'^^'!^*!^^^^!^^!!!^!"^"!!!^!409 


CONTENTS.  xiii 

CHAPTER   XXIY. 

RELAPSING    FEVER. 

Morphology  of  Spirillum 411 

Changes  iu  the  Blood 413 

Bibliography 413 


CHAPTER  XXV. 

MISCELLANEOUS   PARASITIC    DISEASES. 

Trichina  Spiralis 415 

Distoma  Hematobium 416 

Ascaris  Lumbricoides,  Anguilulla  Stercoralis 417 

Anchylostoma  Duodenale,  Bothriocephalus  Latus 418 

Filariasis 421 

Bibliography 423 


LIST  OF  PLATES. 


PLATE.  PAGE. 

I.     Normal  blood.     Triacid  stain 82 

II.     Normal  blood.     Eosin  and  Metbylene-blue 106 

III.  Mild  Chlorosis 164 

IV.  Severe  Chlorosis 169 

V.     Progressive  pernicious  anemia 188 

VI.     Secondary  pernicious  anemia 190 

VII.     Myelemia 211 

VIII.     Lymphemia 215 

IX.     Degenerating  leucocytes  in  leukemia 213 

X.     Mast-cells.     Glycogen  in  leucocytes 252 

XI.     Tertian  malarial  parasite 382 

XII.     Quartan  parasite 388 

XIII.  Estivo-autumnal  parasite 390 

XIV.  Conjugating  cycle  of  tertian  parasite 400 


INTRODUCTORY. 


ON    THE    INTERPRETATION    OF  ANALYSES   OF    THE    BLOOD. 

Plethora. — Although  the  older  physicians  regarded  the  existence  of 
a  true  plethora  as  an  important  and  well-established  fact  in  pathology, 
this  view,  lacking  proof,  received  a  serious  blow  from  the  work  of 
Lud wig's  pupils,  v.  Lesser  and  Worm-Muller,  and  from  the  authorita- 
tive conclusion  of  Cohnheim.  Lesser  and  Worm-Muller,  attempting  to 
produce  artificial  plethora  by  transfusion  of  blood  in  animals,  found 
that  when  the  red  cells  were  thereby  increased  28  percent  the  num- 
bers fell  to  normal  on  the  following  day,  and  when  increased  58  per- 
cent, the  blood  became  normal  on  the  twenty-third  day,  while  the  total 
quantity  of  blood  might  be  doubled  without  abnormal  symptoms,  owing 
to  the  rapid  return  to  the  normal  quantity.  Likewise  Hamburger  was 
unable  to  produce  a  permanent  plethora  in  horses,  by  the  injection  of 
large  quantities  (7  1.)  of  5-percent  solution  of  sodium  sulphate,  finding 
that  the  isotonic  power  of  the  blood,  thus  increased,  became  normal  in 
one-half  to  two  hours,  while  nearly  all  traces  of  the  salt  disappeared 
from  the  blood  in  twenty-four  hours.  Instead  of  drawing  from  these 
data  the  conclusion  that  continuous  plethora  cannot  be  induced  arti- 
ficially, the  unwarranted  claim  was  advanced  that  a  true  plethora  does 
not  exist  (cf.  v.  Recklinghausen,  Lukjanow).  Against  this  conclusion 
stood  the  daily  observation  of  clinicians  and  pathologists,  at  the  bed- 
side and  in  the  dead-house,  that  there  are  extreme  variations  in  the 
quantity  of  blood  in  the  vessels  of  different  subjects,  in  divers  states 
of  health  and  disease.  Oertel  especially  strongly  maintained,  without 
being  able  to  ofPer  proof,  that  the  volume  of  blood  might  be  reduced  in 
endocarditis  and  with  good  therapeutic  effect.  Positive  data  on  the 
question  were  gathered  by  Bergmann  and  Heissler,  pupils  of  Bollinger, 
and  the  fact  established  that  there  is,  in  general,  a  direct  ratio  between 
the  volume  of  blood  and  size  of  the  heart,  and  the  muscular  develop- 
ment of  the  subject,  and  an  indirect  ratio  with  the  subject's  fat-de- 
posits. Though  lacking  full  experimental  proof  it  is  now  generally 
accepted  that  the  quantity  of  blood  in  the  body  is  variable,  may  be  in- 
creased by  hygienic  measures,  and  is  diminished  in  many  unhygienic 
and  diseased  conditions. 

Anhydremia,  /.  e.,  a  reduction  in  the  volume  of  blood  with  concen- 
tration of  solids,  must  be  admitted  to  result  from  loss  of  body  fluids, 
as  by  sweating  and  diarrhea,  or  by  diminished  ingestion  of  water. 

Czerny  exposed  cats  in  a  warm,  dry  chamber  for  36  hours,  finding 
that  they  lost  45  percent  of  their  weight,  the  volume  of  blood  was 
2 


18  INTRODUCTORY. 

greatly  reduced,  its  viscosity  increased,  and  the  red  cells  rose,  in  one 
case,  to  ten  millions  per  cubic  millimeter. 

Grawitz  found  that  profuse  sweating  is  followed  in  the  majority 
of  cases  by  a  concentration  of  the  blood,  in  one  instance  from  s.  g. 
1040  to  1051.  A  few  subjects  showed  a  contrary  reaction  and  dimi- 
nution in  gravity  (1060-1057.5),  which  Grawitz  refers  to  nervous  in- 
fluences. 

Limbeck  examined  the  blood  of  a  case  of  cirrhosis  of  the  liver  with 
extreme  ascites,  before  and  after  tapping  the  abdomen.  On  the  day 
after  the  removal  of  18  1.  of  fluid  the  red  cells  had  risen  from 
3  280,000  to  5,160,000.  Stintzing  and  Gumprecht  have  made  similar 
observations,  before  and  after  the  removal  of  large  serous  exudates. 

Grawitz  found  the  specific  gravity  of  the  blood  at  first  decreased  by 
the  intravenous  injection  of  concentrated  salt  solutions  (absorption  of 
water),  while  the  administration  of  the  salt  by  mouth  concentrated 
the  blood. 

It  therefore  follows  that  the  ingestion  of  water  and  the  loss  of  body 
fluids  always  produces  a  more  or  less  transitory  eifect  on  the  volume 
of  the  blood.  There  can  be  no  doubt  also  that  the  prolonged  sweats  of 
phthisis  and  the  severe  diarrhea  of  typhoid  fever,  dysentery,  and 
cholera,  lead  to  a  more  or  less  continuous  reduction  in  the  volume  of 
the  blood  and  a  concentration  of  blood  cells. 

A  very  striking  illustration  of  this  principle  was  frequently  encountered 
by  the  writer  among  the  soldiers  at  Camp  Wickoff  (1898).  When  these  pa- 
tients, suffering  from  prolonged  malaria  with  severe  anemia  were  attacked 
by  typhoid  fever  or  acute  dysentery,  the  ordinary  watery  character  of  the 
expressed  blood  drop  disappeared,  and  the  blood  soon  became  thick^and 
deep  red. 

Herz  claims  to  have  recognized  an  "  acute  swelling "  of  the  red 
cells  in  febrile  conditions,  especially  in  typhoid  fever,  and  v.  Limbeck, 
finding  a  considerable  average  increase  in  the  volume  of  the  red  cells 
in  eight  febrile  cases,  believes  that  relative  oligoplasmia  with  increased 
volume  of  red  cells  is  of  frequent  occurrence  in  high  fevers. 

The  effect  of  nervous  influences  in  altering  the  quality  of  the  blood 
in  the  Avhole  or  a  part  of  the  circulation  has  been  demonstrated  by 
numerous  studies. 

Cohnstein  and  Zuntz  found  that  section  of  the  cord  above  the  origin 
of  the  splanchnic  nerves  is  followed  by  general  dilatation  of  blood- 
vessels, and  reduction  in  the  proportion  of  red  cells. 

Grawitz  and  Knopfelmacher  found,  in  general,  that  vaso-motor  paral- 
ysis is  followed  by  local  and  general  increase  in  the  volume  of  blood 
with  diminished  specific  gravity  and  proportion  of  red  cells,  while  the 
opposite  effects  follow  vaso-motor  constriction  of  vessels. 

The  nervous  stimulus  of  cold  baths  has  been  found  by  Leichten- 
stern,  Wick,  Knopfelmacher,  Winternitz,  Thayer,  and  Grawitz,  to  be 
followed  by  contraction  of  vessels  and  increase  in  the  proportion  of 
red  and  white  cells,  while  the  hot  pack,  and  the  inhalation  of  amyl 
nitrite,  have  an  opposite  effect. 


INTERPRETATIOy   OF  ANALYSES   OF  THE  BLOOD.  19 

To  a  similar  origin  Diust  be  attributed  the  increased  gravity  of  the 
blood  observed  by  Grawitz  after  the  injection  of  tuberculin,  and  cul- 
tures of  the  bacillus  of  cholera  and  that  of  diphtheria,  and  the  oppo- 
site effect  produced  by  streptococcus  and  staphylococcus  pyogenes,  and 
/>.  anthracis. 

The  influence  of  psychical  emotions  on  the  character  of  the  blood 
in  different  regions  of  the  body  has  been  emphasized  by  Lloyd  Jones, 
and  is  seen  especially  in  the  study  of  the  blood  in  neurotic  women. 
Jacobi,  examining  the  blood  of  an  hysterical  Moman,  found  on  No- 
vember 12th,  3,892,000  red  cells;  on  December  11th,  8,084,000 
red,  102,200  white  cells;  on  December  16th,  3,393,000  red,  22,000 
white.  Grawitz  refers  to  the  remarkable  increase  seen  in  the  specific 
gravity  and  proportion  of  cells  in  the  blood  of  rabbits,  in  experiments 
conducted  without  anesthesia.  The  remarkable  variations  in  the 
blood  taken  from  the  ears  of  rabbits,  depending  on  the  temperature 
and  blood  content  of  the  member,  are  a  matter  of  common  observation. 

In  the  mechanism  by  which  these  changes  are  brought  about,  there 
appear  to  be  many  factors.  Heidenhain,  LoAvit,  Gartner  and  Romer, 
find  that  many  substances  injected  into  the  blood  cause  an  increased 
flow  of  lymph.  (Extract  of  cancerous  tumors,  pepton,  tuberculin, 
toxines  of  B.  pyocyaneus  and  pneumococcus,  hemialbumose,  nuclein, 
uric  acid,  etc.)  Heidenhain  and  Hamburger  believe  that  some  sub- 
stances excite  a  secretory  action  of  the  capillary  endothelium, 
whereby  the  fluids  of  the  blood  are  diminished. 

Grawitz  explains  the  concentration  of  the  blood  under  the  influence 
of  cold  by  the  escape  of  fluids  into  the  tissues,  but  the  experiment  of 
Cohnstein  and  Zuntz  offers  another  explanation,  since  they  found  un- 
der the  microscope  that  capillaries  might  be  so  reduced  in  calibre  by 
irritation  of  vaso-constrictor  nerves  that  no  red  cells,  but  only  plasma, 
could  pass  in  them.  It  then  appears  that  many  red  cells  may  be  caught 
in  the  contracted  capillaries  while  the  plasma  passes  on  into  the  veins. 
Grawitz  has  shown  by  many  comparative  tests  that  the  capillary 
blood  is,  in  all  ordinary  conditions,  richer  in  cells  than  that  of  the 
veins.  It  does  not  appear  to  have  been  proven  that  the  vascular 
dilatation  produced  by  heat  is  followed,  in  this  particular  condition, 
by  the  return  of  tissue  fluids  into  the  capillaries.  It  appears  quite 
as  likely  that  an  irregular  distribution  of  cells  and  plasma  is  to  a  larger 
extent  responsible  for  such  local  variations  in  the  composition  of  the 
blood  (cf.  Winternitz). 

The  law  that  increased  blood  pressure  leads  to  transudation, 
authoritatively  stated  by  Ludwig  and  Landois,  appears  to  have  a  less 
important  application  here  than  in  more  general  and  more  prolonged 
processes.  It  is  not  likely  that  a  cold  bath  can  be  followed  by  much 
exudation  of  serum  into  the  tissues. 

Massage  and  electricity  have  been  shown,  by  Mitchell  and  Cheron, 
to  cause  an  immediate  increase  in  the  number  of  red  cells  in  the  blood 
of  a  part,  an  effect  which  may  be  explained  according  to  the  above 
data. 


20  INTRODUCTORY. 

The  importance  of  the  osmotic  relations  of  the  blood  in  control- 
ling the  volume  of  red  cells  and  plasma,  is  indicated  from  the  discus- 
sion in  Chapter  II.  In  hydremia  and  anhydremia  Hamburger  has 
shown  that  the  isotonic  relations  of  the  blood  are  maintained  by  a 
rapid  interchange  of  salts  and  albumens  between  the  cells  and  plasma, 
with  frequent  minor  changes  in  their  relative  volume.  From  Lim- 
beck's analyses  of  venous  and  arterial  blood  it  appears,  also,  that  the 
imbibition  of  CO2  causes  swelling  of  red  cells  with  absorption  of  water 
and  salts  and  with  relative  diminution  in  the  volume  of  plasma. 


The  foreo-oing  considerations  are  dwelt  upon  not  only  because  of 
their  theoretical  interest,  but  because  they  deal  with  fundamental  facts 
without  the  knowledge  of  which  it  is  impossible  to  properly  perform 
or  sensibly  interpret  the  results  of  an  examination  of  the  blood. 

To  summarize  the  discussion,  it  has  been  shown  that  there  are  wide 
variations  in  the  quantity  and  quality  of  the  blood  referable  to  di- 
verse conditions  other  than  disease. 

1.  There  are  considerable  physiological  variations  in  the  volume 
and  composition  of  the  blood,  according  to  the  constitution  of  the  in- 
dividual (plethora),  and  the  degree  of  muscular  development.  Here 
may  be  classed  the  variations  between  the  sexes  and  between  different 
periods  of  life.  Such  variations  are  permanent  but  usually  not  of 
extreme  grade. 

2.  There  is  a  great  variety  of  physiological  conditions  producing 
marked  but  transitory  changes  in  the  blood,  such  as  active  digestion, 
muscular  exertion,  the  ingestion  of  fluids,  profuse  perspiration,  tem- 
porary cyanosis,  etc. 

3.  The  nervous  system  has  a  very  striking  temporary  influence  on 
the  quality  of  the  blood  in  local  or  general  areas,  acting  through  the 
cerebral  (psychical)  or  medullary  centers,  or  through  local  vaso-motor 
nerves. 

4.  Various  local  influences  may  greatly  change  the  quality  of  the 
blood  specimen,  as  seen  in  the  local  and  transient  effects  of  cold,  heat, 
massage  and  electricity. 

5.  Many  therapeutic  procedures  may  temporarily  alter  the  blood, 
as  the  aspiration  of  fluids,  administration  of  diaphoretics,  purges, 
vaso-dilators  (amyl  nitrite),  vaso-constrictors,  etc. 

6.  Various  pathological  conditions  may  partly  or  completely  ob- 
scure the  real  status  of  the  blood,  as  the  sweats  of  phthisis  ;  the  diar- 
rhea of  typhoid  fever,  dysentery,  and  cholera;  general  cyanosis  or 
local  stasis  ;  the  increased  arterial  tension  of  uremia ;  the  polyuria  of 
diabetes  and  nephritis ;  antemortem  cardiac  failure,  etc. 

Having  regard  to  the  possible  action  of  any  of  the  above  influences, 
one  may  avoid  many  of  the  local  disturbances  by  observing  special 
care  in  the  manner  of  expressing  the  blood  specimen. 

The  blood  should  be  expressed  by  very  slight  pressure,  exerted  at  a 
distance,  from  a  liberal  puncture  of  the  finger-tip  or  ear-lobe.     The 


INTERPRETATION  OF  ANALYSES   OF  THE  BLOOD.  21 

circulation  in  the  part  should  be  as  nearly  normal  as  possible  and 
should  be  uniform.  A  cold  bloodless  tissue  is  not  suitable  for  furnish- 
ing a  blood  specimen,  and  if  artificial  means  are  taken  to  correct  the 
condition  a  sufficient  period  must  elapse  to  allow  the  accelerated  circu- 
lation to  subside.  Blood  should  be  taken  not  less  than  four  hours  after 
a  hearty  meal,  and  when  comparative  tests  are  made,  the  specimens 
should  be  taken  at  the  same  hour  each  day. 

The  examination  having  been  performed,  its  results  are  to  be  inter- 
j)j'eted  only  in  the  light  of  the  fullest  possible  clinical  information.  There 
can  be  no  doubt,  as  GraAvitz  has  pointed  out,  that  the  numerous  con- 
tradictory results  of  hematological  studies  are  largely  referable  to 
hasty  conclusions  drawn  from  figures  without  regard  to  the  condition 
of  the  patient  or  the  stage  of  the  disease  under  consideration.  Like- 
wise, hematological  diagnosis  has  fallen  into  much  discredit  from  the 
tendency  to  offer  opinions  from  the  isolated  findings  of  the  blood-test. 


PART  I. 
GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 

CHAPTER   L 
TECHNICS. 

QUALITATIVE    TESTS    FOR    BLOOD. 

By  far  the  most  delicate  test  for  blood  is  the  demonstration  of  red 
blood  cells  under  the  microscope,  but  as  these  cells  are  not  always 
preserved  in  demonstrable  form,  one  must  frequently  resort  to  various 
tests  for  hemoglobin  and  its  derivatives. 

The  Guiacum  Test. 

To  a  watery  solution  of  the  suspected  substances  is  added  a  few 
drops  of  tincture  of  guiac,  producing  a  milky  precipitate.  A  few 
drops  of  hydrogen  peroxide 

added  will,  in  the  presence  Fig.  1. 

of  blood  pigment,  produce 
a  distinct  blue  color. 

The  tincture  of  guiac 
should  be  freshly  made,  and 
diluted  to  the  color  of  pale 
sherry  wine.  The  guiac 
must  be  added  before  the 
peroxide,  and  the  blue  color 
must  develop  immediately. 
Many  substances  turn  tinc- 
ture of  guiac  blue,  without 
the  presence  of  peroxide. 
This  test  is  very  delicate, 
demonstrating  one  part  of 
fresh  blood  in  several  thou- 
sand of  water.  It  is  most 
effective  with  fresh  speci- 
mens ;    but    after    two    or 

three  years  some  specimens  fail  to  react  satisfactorily.  Brandenburg 
finds  that  leucocytes  of  myelogenous  origin,  but  not  the  lymphocytes 
give  this  same  reaction. 


Hemin  crystals.     (Riedek.  ) 


24 


GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 


The  Hemin  Test  (Teichmann's). 

A  drop  of  blood  or  portion  of  suspected  detritus  is  spread  out  on 
a  glass  slide  mixed  with  one  drop  of  salt  solution  and  dried  at  a  low 
temperature.  A  cover-glass  is  then  laid  over  the  specimen,  filled 
beneath  with  glacial  acetic  acid,  and  the  specimen  evaporated  with 
higher  heat,  but  without  boiling.  When  the  fluids  have  entirely 
evaporated,  the  specimen  may  be  mounted  in  distilled  water  and  ex- 
amined microscopically  for  the  characteristic  crystals  of  hemin 
(Teichmann's  crystals). 

The  hemin  test,  if  successful,  is  absolutely  reliable,  but  often  fails, 
in  unskilled  hands,  from  (1)  Alteration  of  albumins  by  excessive 
heat,  preventing  the  formation  of  crystals  ;  (2)  Excess  of  salt  solution  ; 
(3)  Violent  boiling  which  drives  off  free  HCl,  thus  preventing  the 
formation  of  hemin  crystals  (hydrochloride  of  hematin). 


SPECTROSCOPIC    EXAMINATION    OF    BLOOD. 

In  all  cases  where  a  sufficient  quantity  of  dissolved  blood  can  be 
obtained  for  examination  the  spectroscopic  test  is  the  best  means  of 
determining  not  only  the  presence  of  blood  pigment  but  also  its  par- 
ticular form. 

Of  fresh  blood  a  1 -percent  solution  yields  very  distinct  absorption 
bands.  Recently  clotted  blood  dissolves  readily  in  water.  Old  clots 
may  usually  be  dissolved  by  maceration  in  acetic  acid  after  which  the 
spectrum  of  acid  hematin  is  obtained.  Clots  that  have  been  exposed 
to  heat  must  be  macerated  in  ammonia,  when  the  spectrum  of  reduced 

or    of   alkaline    hematin 
Fig.  2.  will  result. 

For  ordinary  clinical 
Avork  Browning's  spectro- 
scope is  very  satisfactory, 
but  absorption  bands  are 
more  accurately  located  in 
larger  instruments.  The 
small  instrument  should 
be  supported  in  a  con- 
venient holder  in  strong 
daylight  or  gaslight.  By 
means  of  a  collar  the 
width  of  the  aperture 
may  be  varied  according  to  the  strength  of  the  light  and  opacity  of 
the  fluid.  By  means  of  the  sliding  tube  Fraunhofer's  lines  are  brought 
mto  accurate  focus.  The  fluids  should  be  examined  in  small  glass  vials 
with  flat  sides. 

When  dealing  with  fresh  blood  and  unaltered  Hb  the  spectrum  is 
that  of  oxyhemogJoh'in,  which  shows  two  absorption  bands  between  D 
and   E,  one  rather  thin  and  sharp  near  the   orange,  and  the  other 


T.n 'Wiiing's  si)ectroscoi)e. 


SPECTROSCOPIC  EXAMINATION  OF  BLOOD. 


25 


broader  near  the  green.  The  indigo  and  most  of  the  blue  is  absorbed. 
In  strong  solution  the  two  bands  of  ox_yhemoglobin  may  be  united. 

If  to  the  solution  of  oxyhemoglobin  is  added  a  little  reducing  sub- 
stance, such  as  ammonium  sulphide,  the  color  of  the  fluid  becomes 
darker  and  the  spectrum  changes,  becoming  that  of  reduced  hemoglobin, 
giving  one  broad  absorption  band  between  D  and  E. 

The  transformation  of  the  spectrum  of  oxyhemoglobin  to  that  of  re- 
duced Hb,  by  reducing  agents,  is  the  positive  indication  of  the  presence 
of  blood.  Cochineal  and  ammouiated  carmine  give  spectra  very  simi- 
lar to  that  of  oxyhemoglobin,  but  on  the  addition  of  boracic  acid  the 
spectra  of  these  substances  are  displaced  into  the  blue,  while  that  of 
blood  remains  unaffected.  The  spectra  of  various  other  vegetable  dyes 
simulate  that  of  blood  but  these  are  bleached  by  sodium  bisulphite. 

Hematin  is  produced  by  the  addition  of  acids  or  strong  alkalies  to 


Fig.  3. 


Red 


Orange    YeUoiv 
B    C  D 


Green 
Eh 


Blue 


Indigo 
G 


!! 


Oxtjlicemoglobin 


Reduced 
H(jemoglobin 

Meduced 
Hcematin 

Methcfmnglobiil 
Acid 


Co-Haemoglobin 

Hcematin 
Alkaline 


I 


Spectra  of  blood  pigments.    (After  Limbeck.) 

reduced  Hb.  In  acid  solution  its  spectrum  is  similar  to  that  of  acid 
methemoglobin.  In  alkaline  solution  it  gives  a  single  rather  broad 
band  at  jD. 

Clinically,  the  most  important  alteration  of  oxyhemoglobin  is  that 
into  methemoglobin,  sometimes  detected  by  the  chocolate  color  of  the 
blood.  In  acid  or  neutral  solution  it  gives  four  absorj)tion  bands,  one 
quite  sharp,  between  Cand  J);  a  second,  faint,  in  the  yellow,  immedi- 
ately to  the  right  of  D ;  a  third,  broad,  rather  distinct,  between  the 
yellow  and  green,  and  just  to  the  left  of  E;  a  fourth,  broad,  to  the  left 
of  F,  sometimes  merged  with  a  complete  absorption  of  the  blue  end  of 
the  spectrum. 

The  demonstration  of  carbonic-oxide-Hb  is  of  great  clinical  impor- 
tance in  cases  of  gas-poisoning.  The  blood  drop  has  a  rosy  red  tinge, 
seen  alike  in  both   venous  and  arterial  blood.     In  one-half  percent 


26  GENERAL  PHYSIOLOGY  AND   PATHOLOGY. 

dilution  a  spectrum  is  obtained  which  resembles  that  of  oxyhemoglobin, 
but  the  bands  are  broader,  and  the  D  band  is  displaced  slightly  to  the 
right.  On  the  addition  of  ammonium  sulphide  the  spectrum  of  oxy- 
hemoglobin is  replaced  by  that  of  reduced  Hb,  while  Co-Hb  remains 
unaltered.  In  applying  this  test  clinically,  since  considerable  oxyhemo- 
globin remains  in  the  blood  in  most  cases,  the  results  of  spectral 
analysis  are  not  always  clear,  and  corroborative  tests  are  required. 

1.  \yarm  the  specimen  with  equal  parts  of  10-percent  NaOH ; 
normal  blood  becomes  dark  brownish  green,  the  other  becomes  cloudy, 
then  clear  red,  and  red  flakes  gather  on  the  surface.     (Hoppe-Seyler.) 

2.  To  a  2-percent  solution  of  blood  add  a  few  drops  of  orange-col- 
ored ammonium  sulphide  containing  an  excess  of  sulphur,  and  faintly 
acidify  with  a  few  drops  of  dilute  acetic  acid,  carefully  shaking.  Car- 
bonic-oxide blood  then  shows  a  beautiful  rose  red  color,  with  a  floc- 
calent  precipitate,  while  normal  blood  becomes  greenish  or  reddish 
gray.  The  test  may  be  performed  in  a  porcelain  dish,  adding  a  drop 
of  blood  to  the  mixed  reagents.     (Katayama.) 

Kunkel  and  Welzel  employ  a  solution  of  zinc  chloride,  or  very 
dilute  solution  of  platinum  chloride,  which  color  carbonic-oxide  blood 
bright  red,  normal  blood,  black. 

Rubner  recommends  that  the  suspected  blood  be  diluted  4-5  times 
with  acetate  of  lead,  when  normal  blood  becomes  chocolate,  carbonic- 
oxide  blood  red. 

Watery  neutral  solutions  of  Co-Hb,  boiled,  yield  a  clear  red  coagu- 
lum,  while  oxyhemoglobin  becomes  grayish  brown.      (Hoppe-Seyler.) 

Estimation  of  Total  Quantity  of  Blood. 

The  limits  of  error  in  the  methods  of  estimating  the  total  quantity 
of  blood,  suggested  by  Valentin,  Vierordt,  Buntzen,  and  Thibault, 
probably  exceed  the  physiological  and  pathological  variations  in  the 
bulk  of  this  tissue,  and  are  therefore  not  available  for  clinical  purposes. 

ESTIMATION  OF  THE    VOLUME  OF  RED   CELLS    AND  PLASMA. 
THE    HEMATOCRIT. 

The  idea  that  the  centrifuge  might  give  valuable  clinical  information 
concerning  the  volume  of  red  cells  was  original  with  Blix,  while  his 
instrument  and  method  have  been  improved  principally  by  Hedin, 
Gartner,  and  Daland.  Although  hand-centrifuges  have  been  used  and 
recommended,  the  best  results  are  obtained  only  with  the  electric  cen- 
trifuge, which  is  at  present  in  the  market  at  a  reasonable  figure. 

The  improved  electric  centrifuge  consists  of  an  iron-clad  motor  car- 
rymg  a  steel  shaft  and  horizontal  armature  for  urine  tubes,  which  may 
be  replaced  by  the  hematocrit.  A  "  speed  indicator  "  may  also  be 
attached  which  strikes  a  bell  with  every  100  revolutions.  The 
instrument  is  practically  noiseless  even  with  a  very  high  speed.  A 
rheostat  is  used  to  control  the  current  and  speed.      A  speed  of  8,000- 


THE  HEMATOCRIT. 


27 


Fig.  4. 


10,000  revolutions  may  be  obtained  by  a  small  battery  or  from  the 
street  current.  The  hand-centrifuge,  Fig.  5,  may  be  employed  when 
it  is  not  convenient  to  use  electricity. 

The  hematocrit-attachment  consists  of  two  capillary  tubes,  graduated 
in  100  degrees,  which  are  held  in  the  armature  by  springs.     (Fig.  5.) 

Procedure. — With  walking  patients  fresh  blood  may  be  used. 
The  capillary  tubes  may  be  filled  automatically  by  holding  the  tube 
horizontally,  or  with  one  end  slightly  depressed,  and  touching  it  to 
the  rather  large  drop  of  blood  required.  The  tube  is  then  immedi- 
ately inserted  in  the  armature,  as  in  Fig.  5,  the  opposite  tube  hav- 
ing previously  been  filled  with  water,  and  the  revolutions  are  begun 
before  the  blood  coagulates. 

When  the  patient  is  at  a  distance,  the  blood  must  be  diluted,  prefer- 
ably in  2.5-percent  solution  potassium  bichromate,  as  recommended 
by  Daland.  The  blood  should  be 
diluted  with  equal  parts  of  this 
solution,  which  may  be  accom- 
plished in  the  red-cell  or  white- 
cell  pipette  of  the  hemocy  tometer. 
With  the  red-cell  pipette  the  cap- 
illary tube  is  filled  with  blood  to 
the  mark  1,  then  a  small  air  bub- 
ble is  drawn  in,  followed  by  an- 
other tube-length  of  blood.  Three 
or  four  tube-lengths  of  blood 
should  be  secured  in  this  way 
and  immediately  mixed  with  an 
equal  number  of  tube-lengths  of 
diluent.  With  the  white-cell 
pipette  a  single  measure  of  blood 
and  diluent  is  sufficient.  The 
blood  and  diluent  should  then  be 
mixed  by  gentle  shaking,  taking 
care  not  to  enclose  air  bubbles. 
When  diluted  blood  is  used  both 
tubes  of  the  hematocrit  should  be 
filled  with  blood,  which  may  be 
done  by  allowing  the  drops  to  flow 
in  from  the  point  of  the  pipette. 

The  tubes  are  now  revolved 
at  a  speed  of  eight  to  ten  thou- 
sand revolutions  per  minute,  for 
three  minutes,  after  which  the 
volume  of  the  red  cells  has  been 
found  unalterable. 

The  question  now  arises  how  many  red  cells  are  contained  in  one 
degree  of  the  scale.  Daland,  working  extensively  with  diluted  blood, 
places  the  number  at  99,390,  practically  100,000. 


Inil)r<)vetl  olectric  hematocrit,  with  fender,  rheo- 
stat, and  speed-indicator.  The  hematocrit  attach- 
ment replaces  the  urine  tubes  seen  in  the  revolving 
armature. 


28 


GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 


Cabot,  in  a  series  of  40  comparative  tests,  using  undiluted  blood  in 
the  hematocrit,  found  variations  between  105,000  and  123,000,  with 
an  average  of  112,000. 

Further  observations  on  this  point  are  required,  but  at  present  the 
above  figures  should  be  used  for  diluted  and  fresh  blood  respectively, 
multiplying  the  result  by  two  Avhen  diluted  blood  has  been  used. 

Fig.  5. 


Daland's  hematocrit. 


Limitations  of  the  Hematoceit. — Since  the  centrifuge  does 
not  necessarily  require  the  use  of  diluting  fluids,  a  serious  cause  of 
error  in  the  method  may  be  removed  by  the  use  of  fresh  blood.  It 
must  be  admitted,  however,  that  the  original  volume  of  the  red  cells 
cannot  always  be  exactly  determined  by  this  method,  as  in  pathological 


THE  HEMATOCRIT.  29 

conditions  the  compressibility  of  the  corpuscles  is  not  always  uniform. 
Moreover,  in  altered  conditions  of  the  plasma,  it  is  uncertain  how 
much  change  can  be  wrought  in  the  natural  volume  of  red  cells  by 
violent  centrifugal  force.  Some  fragile  cells  are  probably  always  de- 
stroyed during  the  centrifugal  process. 

When  diluting  fluids  are  used,  the  error  is  doubtless  increased  by 
alterations  in  the  density  and  composition  of  the  plasma  and  in  the 
volume  of  the  red  cells  caused  by  the  action  of  the  fluid.  Neverthe- 
less Daland's  claim  must  be  admitted  that  the  volume  of  the  red  cells, 
except  in  leukemia,  is  determined  by  this  method  with  accuracy  suf- 
ficient for  clinical  purposes.  The  value  of  such  information  is,  of 
course,  quite  evident. 

The  further  claim  that  the  hematocrit  may  give  more  accurate  esti- 
mates of  the  number  of  red  cells  than  does  the  hematocytometer  has 
not  been  confirmed.  The  volume  of  the  red  cells  differs  so  markedly 
in  both  the  chlorotic  and  the  pernicious  anemias  that  one  cannot  seri- 
ously consider  the  project  of  replacing  the  hematocytometer  by  the 
hematocrit.  Only  in  the  moderate  secondary  anemias,  with  little 
change  in  the  size  and  Hb-content  of  the  cells,  can  the  volume  of  the 
red  corpuscles  yield  reliable  indications  of  their  number.  In  cases  of 
leukemia  and  of  extreme  leucocytosis  so  many  leucocytes  are  entangled 
with  the  red  cells  that  even  the  volume  of  the  red  cells  is  not  accu- 
rately told,  much  less  their  number.  Each  of  these  instruments  has 
its  proper  field  to  which  it  should  be  restricted,  and  as  the  hematocrit 
is  not  over-exact  in  its  immediate  object,  it  is  unscientific  to  introduce 
a  second  source  of  error,  as  is  done  in  attempting  to  compute  the  num- 
ber of  red  cells  from  their  volume. 

It  may  be  added  that  the  value  of  the  hematocrit  in  estimating  the 
character  and  severity  of  an  anemia  has  not  yet  been  as  fully  recog- 
nized by  clinicians  as  it  deserves,  possibly  because  more  attention  has 
been  paid  to  the  number  of  red  cells  than  to  their  functional  capacity. 

The  reliability  of  the  centrifuge  in  determining  even  the  volume  of 
the  red  cells  has  been  denied  principally  by  the  brothers  Bleibtreu, 
and  by  Bleibtreu  and  Wendelstadt.  These  observers  devised  another 
method  of  determining  the  volume  of  the  red  cells,  which  they  claim 
gives  more  trustworthy  results  than  are  obtained  by  the  hematocrit. 
They  employed  .6-percent  salt  solution  to  prevent  coagulation  and 
allowed  the  blood  to  settle  slowly.  The  nitrogen-content  of  the  super- 
natant plasma  was  then  determined  by  Kjeldahl's  method,  and  from  tables 
which  these  observers  constructed  the  volume  of  the  plasma  and  hence 
that  of  the  red  cells  could  be  determined,  from  the  quantity  of  N  obtained. 

While  the  results  obtained  with  the  hematocrit  by  several  observers 
indicate  that  the  normal  volume  of  red  cells  varies  between  40-66 
percent,  Bleibtreu's  method  gave  normal  variations  in  cadaveric 
blood  between  25.15  and  55.8  percent  (Bleibtreu,  Pfeiffer),  v.  Lim- 
beck obtained  very  low  volumes  with  Bleibtreu's  method  (24-28  per- 
cent) which  he  refers  to  the  use  of  highly  oxidized  blood,  in  which 
he  believes  the  red  cells  are  reduced  in  volume.     The  lengthy  discus- 


30 


GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 


sion  which  has  prevailed  regarding  the  above  points,  indicates  that 
the  vokimc  of  the  red  cells  is  subject  to  a  considerable  variety  of 
changes,  the  origin  and  significance  of  which  are  little  understood.  It 
has  been  shown  that  in  order  to  prevent  N  from  leaving  the  red  cells 
during  sedimentation,  the  exact  isotonic  tension  of  the  plasma  must  be 
determined  in  each  instance,  and  a  corresponding  solution  of  salt  used. 
The  isotonic  tension  of  plasma  is  rarely  so  low  as  .G-percent  NaCl. 

Moreover,  supposing  that  the  red  cells  remain  intact  during  sedi- 
mentation, the  pathological  variations  in  the  N-content  of  the  plasma, 
depending  on  several  variable  nitrogenous  bodies,  are  too  frequent  and 
marked  to  permit  of  any  fixed  formula  to  give  the  volume  of  the  serum 
from  its  content  of  nitrogen.  (Bleibtreu's  method  has  been  sharply 
criticised  by  Hamburger,  Eyckman,  Hedin,  Biernacki  and  others.) 

The  following  table  of  results  obtained  by  Biernacki  well  illustrates 
the  unreliability  of  comparisons  between  results  obtained  by  different 
procedures  and  the  general  inaccuracy  of  all  indirect  methods  of  esti- 
mating the  number  of  red  cells  or  percentage  of  Hb,  from  the  volume 
of  the  cells  and  the  specific  gravity  : 


Case. 


Content  of 
water. 


Red  Cells. 


Number.      Volume  f. 


Hb. 


Normal 

Normal 

Cancer  Esophagus 

Kheumatism 

Chlorosis 

Phthisis  

Nepliritis 

Tabes... 

Chlorosis 

Phthisis 

Ulcer  of  Stomach 

Chlorosis 

Nephritis 


77.18% 

77.50 

79.58 

79.02 

80.99 

82.37 

82.73 

83.09 

83.04 

84.59 

85.43 

89.36 

89.46 


037  mil. 

487 

175 

902 

958 

672 

800 

512 

250 

975 

825 

456 

184 


56.3 
53.6 
52.7 
49.1 
50.0 
40.9 
40.0 
47.6 
35.4 
30.9 
37.1 
20.0 
13.6 


105% 
100 

80 

85 

70 

60 

70 

65 

55 

50 

45 

25 

20 


Grawitz  determines  the  volume  of  red  cells  in  blood  drawn  in  con- 
siderable quantities  by  venesection.  The  specific  gravities  of  the  whole 
blood  (Dj),  of  the  centrifuged  serum  {D^,  and  of  the  sedimented  red 
cells  {D^,  are  first  determined,  from  which  the  volume  percentage  of 
red  cells  (;r)  may  be  computed  by  the  following  formula  : 


x=  100 


(A -A) 


ESTIMATION    OF    THE    NUMBER    OF    BLOOD    CELLS. 

The  Hematocytometer. — The  instrument  now  in  use  for  counting 
blood  cells  is  that  of  Thoma,  who  combined  and  improved  several 
features  of  instruments  previously  devised  by  Hayem,  Gowers,  and 
Malassez.  This  apparatus  consists  of  a  mixing  pipette  and  a  counting 
chamber. 


ESTIMATION  OF  THE  NUMBER   OF  BLOOD   CELLS. 


31 


(a)  The  pipette  is  a  capillary  tube  graduated  in  ten  equal  divisions, 
surmounted  by  a  bulb  of  exactly  100  times  the  capacity  of  the  tube,  and 
to  which  is  attached  a  rubber  tube  and  mouthpiece.  (See  sketch.) 
AVhen  the  tube  is  filled  with  blood  up  to  the  mark  1,  and  this  is  mixed 
with  a  diluting  fluid  sucked  up  to  the  mark  101,  a  specimen  of  blood 
is  obtained  in  the  dilution  of  1  to  100.  By  filling  only  one-half  the 
tube  with  blood,  up  to  the  mark  0.5,  the  subsequent  dilution  is  in  the 
proportion  of  1  to  200.  The  bulb  contains  a  glass  ball  to  facilitate 
the  mixing  of  the  blood. 

{b)  The  counting-chamber  is  constructed  so  as  to  secure  a  layer  of 
diluted  blood  J^  millimeter  in  depth  over  a  certain  square  area. 

On  a  thick  glass  slide  is  cemented  a  thinner  glass  plate,  the  central 
portion  of  which  is  cut  out.  In  this  central  area  is  cemented  a  circular 
glass  shelf  the  surface  of  which  is  exactly  J^  millimeter  lower  than 


Fig.  6. 


Tlif  Tlioma  hematocytoineter. 


the  surface  of  the  glass  plate.  When  a  drop  of  diluted  blood  is 
placed  on  the  shelf  and  covered  with  a  cover-glass,  a  layer  of  fluid  is 
secured,  which  is  exactly  J^  millimeter  deep.  Between  the  edge  of 
the  shelf  and  the  surrounding  plate  is  a  moat  into  which  the  blood  may 
run,  but  if  the  fluid  should  run  over  the  moat  and  beneath  the  cover- 
glass,  the  latter  will  be  elevated  and  the  resulting  layer  of  fluid  will 
be  more  than  ^L  millimeter  deep.  The  shelf  is  accurately  ruled  as 
shown  in  Fig.  8. 

The  entire  ruled  area  is  nine  square  millimeters,  but  only  the  cen- 
tral square  millimeter  is  used  in  counting  red  cells,  the  others  being 
required  in  counting  leucocytes.  It  will  be  seen  that  this  central 
square  millimeter  is  subdivided  into  400  small  squares  (1 6  blocks  of 
25  each),  so  that  each  small  square  is  -j^q-  sq.  mm.  Beginning  at  the 
lower  left-hand  corner  of  this  area,  it  will  be  seen  that  every  fifth 
square,  above  and  to  the  right,  is  subdivided  by  an  extra  line,  which 


32  GENERAL  PHYSIOLOGY  AND  PATHOLOGY.  | 

is  added  merely  to  assist  in  counting  the  squares.  The  outlying 
square  millimeters  are  variously  ruled. 

The  above  description  applies  only  to  the  so-called  "  Zappert " 
chamber  Avhich  should  always  be  secured,  preferably  of  Zeiss'  manu- 
facture. The  older  chambers* cannot  well  be  used  for  counting  leuco- 
cytes. 

Diluting  Fluids. — Of  the  various  diluting  fluids,  Toisson's  Mixtuee 
is  to  be  recommended  : 

Sodium  sulphate 8  grrn. 

Sodium  chloride 1 

Glycerin  pur 30 

Aquadest 160  " 

Methyl  violet 025    " 

This  fluid  keeps  well,  stains  the  leucocytes,  and  is  of  high  specific 
gravity  so  that  the  red  cells  settle  from  it  slowly. 

When  counting  leucocytes  only,  one  may  use  with  advantage  a  .6- 
percent  solution  of  sodium  chloride  tinged  with  gentian  violet  (about 
1  drop  of  saturated  alcoholic  solution  gentian  violet  to  50  cc.  of  salt 
solution).  This  fluid,  while  readily  prepared,  does  not  keep  well,  and 
the  red  corpuscles  settle  from  it  so  rapidly  that  it  ought  not  to  be  used 
in  counting  these  cells.  It  permits,  however,  of  the  identification  of 
eosinophile  cells  and  of  certain  degenerative  changes  in  leucocytes. 

A  reliable  fluid  for  diluting  and  permanently  preserving  blood  is 
found  in  Hayem's  Mixture  : 

Hvdrarg.  bichlor 0.5  grm. 

Sod.  sulphat 5.0     " 

Sod.  chlor 1.0     " 

Aq.  dest 200.0     " 

Directions  for  Using  the  Hematocytometer.  (a)  Filling  the  Pi- 
pette.— The  finger  tip  of  the  patient  is  cleansed  with  soap  and  water, 
dried  with  alcohol,  and  freely  punctured  with  a  needle  or  a  specially 
prepared  acne-lancet.  Using  very  gentle  pressure  only,  a  compact 
drop  of  blood  is  then  expressed  and  the  capillary  tube  is  filled  to  the 
mark  1  or  0.5.  In  doing  this  the  pipette  must  be  held  between  the 
thumb  and  forefinger  and  the  hand  steadied  against  the  hand  of  the 
patient.  In  well  constructed  pipettes  the  column  of  blood  is  easily 
controlled,  and  after  filling,  the  end  of  the  tube  may  be  cleansed  of 
adherent  blood.  The  diluting  fluid  is  then  sucked  up  to  the  mark  101, 
taking  care  that  no  blood  runs  out  of  the  tube  when  it  is  immersed  in 
the  fluid.     The  specimen  is  then  thoroughly  mixed  by  shaking. 

(6)  FiLLixG  the  Couxting-chamber. — The  counting-chamber 
and  cover-glass  are  thoroughly  dried  and  freed  from  particles  of 
dust.  One  or  two  drops  of  diluted  blood  are  first  forced  from  the  pi- 
pette and  a  third  drop,  the  size  of  which  can  be  learned  only  by  expe- 
rience, is  deposited  on  the  central  shelf.  The  cover-glass  is  then  im- 
mediately adjusted,  slipping  one  corner  under  the  forefinger  of  the  left 


ESTIMATION  OF  THE  NUMBER   OF  BLOOD   CELLS.  33 

hand  and  controlling  the  opposite  corner  with  the  second  finger  of  the 
right  hand,  and  lowering  the  glass  slowly  so  as  not  to  inclnde  air  bubbles. 
Without  raising  the  fingers,  now  quickly  cover  the  other  corners  with 
the  forefinger  of  the  right  and  second  finger  of  the  left  hand,  and  press 
the  cover-glass  firmly  into  position.  If  the  application  is  successful 
and  no  dust  particles  have  intervened,  Newton's  color  rings  will  appear 
beneath  the  cover-glass.  The  formation  and  permanency  of  these  rings 
may  be  facilitated  by  breathing  very  gently  on  the  specimen  before  ap- 
plying the  cover-glass. 

The  specimen  should  now  be  held  up  to  the  light  and  examined 
closely  to  see  that  the  red  cells  are  evenly  distributed.  An  uneven 
distribution  is  readily  detected  by  the  naked  eye.  After  settling  a  few 
moments  the  specimen  is  ready  for  counting. 

The  rapid  and  successful  adjustment  of  the  cover-glass  is  the  most  im- 
portant detail  in  the  process  of  counting  blood  cells.  The  cover-glass 
must  be  rapidly  adjusted  because  from  the  moment  the  drop  is  placed 
upon  the  shelf  there  is  a  rain  of  cells  upon  the  ruled  area  out  of  a  layer 
of  fluid  which  is  more  than  ^L  mm.  deep. 

The  specimen  must  be  discarded : 

If  Newton's  rings  do  not  appear. 

If  any  air  bubbles  are  inclosed. 

If  the  fluid  runs  underneath  the  cover-glass. 

If  the  shelf  i&  not  well  covered  by  fluid. 

If,  on  inspection,  the  cells  are  found  unequally  distributed. 

(c)  Counting  the  Red  Cells. — The  specimen  proving  satisfactory 
the  count  may  begin  as  soon  as  the  cells  have  settled.  Zeiss,  D., 
Leitz,  No.  7,  Reichert's  or  Bausch  and  Lomb,  ^,  are  the  lenses  best 
suited  for  this  purpose,  and  a  good  mechanical  stage  is  necessary  for 
accurate  work.  Locate  in  the  field  the  lower  left-hand  block  of  25 
small  squares,  begin  at  the  lower  and  left  square  and  passing  to  the 
right  count  all  the  cells  lying  in  the  first  five  squares.  The  fifth 
square  will  be  found  subdivided.  In  each  square  count  all  the  cells 
lying  on  the  lower  and  lefi  side  lines,  leaving  to  be  counted  with  the 
adjacent  squares  all  the  cells  lying  on  the  lines  above  and  to  the  right. 
Proceed  in  this  way  till  at  least  four  blocks  of  25  small  squares,  and 
at  least  1,000  cells  are  enumerated.  The  more  squares  counted  over 
the  greater  the  accuracy,  and  when  slight  variations  are  to  be  demon- 
strated the  entire  square  millimeter  must  be  covered.  If  the  cells  now 
appear  to  be  unevenly  distributed  the  specimen  should  be  discarded 
and  another  prepared  after  thoroughly  shaking  the  pipette. 

(d)  Computation. — Suppose  that  1,280  cells  are  enumerated  in 
100  small  squares,  i.  e.,  in  ^  of  the  square  millimeter.  This  number 
multiplied  by  4  gives  the  number  lying  over  one  square  millimeter. 
But  the  depth  of  the  fluid  is  only  J^  mm.  so  that  we  multiply  again  by 
10  to  get  the  number  of  cells  in  one  cubic  millimeter  of  fluid.  Finally 
we  must  multiply  by  100  because  the  blood  is  diluted  in  the  propor- 
tion of  1  to  100. 

In  short,  after  counting  over  100  small  squares  the  result  is  multi- 
3 


34  GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 

plied  by  4.,000  to  give  the  number  of  cells  per  cubic  millimeter. 
(4  X  10  X  100  =  4,000.) 

If  the  capillary  tube  was  originally  filled  to  the  mark  0.5,  the  di- 
lution is  1-200,  and  the  multiplier  8,000.  If  400  squares  are  counted 
over,  the  multiplier  is  1,000. 

(e)  Sources  of  Error  in  the  Use  of  the  Hematocytometer.  1.  In 
Securing  the  Drop  of  Blood. — When  much  pressure  is  employed 
in  expressing  the  drop  of  blood,  tissue  fluids  are  squeezed  out  with  the 
blood  and  the  number  of  red  cells  is  reduced.  Reinert  found  a  reduc- 
tion of  722,000  from  this  cause,  which  is  especially  potent  in  cases  of 
dropsy  and  of  severe  anemia. 

When  the  finger  is  cold,  the  circulation  poor,  or  local  stasis  is  pro- 
duced, as  by  a  ligature,  the  red  cells  are  increased  in  number.  To 
avoid  errors  of  this  class,  the  circulation  in  the  hand  should  be  as  ac- 
tive as  possible,  the  finger  warm,  and  the  puncture  liberal  enough  to 
permit  the  flow  of  blood  with  little  pressure  applied  at  some  distance 
from  the  puncture.  Unless  these  conditions  can  be  secured  it  is 
hardly  worth  while  to  count  the  blood  cells. 

2.  In  Diluting  the  Blood  and  in  Transferring  it  to  the 
Counting-chamber  there  are  numerous  plainly  evident  sources  of 
error,  such  as  the  inaccurate  filling  of  the  capillary  tube,  the  entrance 
of  air  with  the  blood  column,  the  failure  to  cleanse  the  tip  of  adherent 
blood,  the  escape  of  blood  into  the  diluting  fluid,  the  overfilling  of  the 
bulb  with  diluting  fluid,  the  inadequate  mixture  of  the  blood,  the  fail- 
ure to  discharge  one  or  two  drops  before  applying  one  to  the  shelf,  the 
use  of  thin  cover-glasses,  and,  above  all,  delay  and  inaccuracy  in  ad- 
justing the  cover-glass.  A  little  experience  and  constant  care  serve  to 
eliminate  all  these  difficulties. 

3.  In  the  Construction  and  Condition  of  the  Apparatus. — 
The  tendency  to  favor  the  Zeiss  instruments  is  still  probably  well 
founded,  although  Leitz  and  Reichert  are  now  making  very  excellent 
pipettes  after  Grawitz'  model.  Aside  from  inaccuracies  in  the  gradu- 
ation of  the  pipette  and  construction  and  ruling  of  the  counting-chamber, 
which  are  now  reduced  to  a  minimum,  some  pipettes  are  still  on  sale 
which  are  too  short,  their  calibre  is  too  large  and  is  narrowed  at  the 
point  so  that  the  tubes  cannot  be  cleaned,  they  require  too  much  blood, 
and  the  short  arm  is  so  small  that  the  mark  101  comes  too  close  to  the 
bulb.  Accurate  work  cannot  be  performed  with  such  instruments. 
The  worker  is  at  present  advised  to  insist  on  having  Grawitz'  pipette 
made  by  Zeiss,  Leitz,  or  Reichert. 

Many  close  observers  find  that  their  pipettes  vary  with  the  temper- 
ature. While  accurate  information  on  this  point  is  not  at  hand  it  is 
just  as  well  to  avoid  extremes  of  temperature  in  making  the  tests  and 
in  cleaning  the  instrument.  It  has  been  suggested  that  the  polycy- 
themia of  high  altitudes  is  partly  referable  to  variations  in  the  hemo- 
cytometer  due  to  changes  in  atmospheric  pressure,  but  this  suspicion 
has  not  been  confirmed. 

The  condition  of  the  pipette  is  of  prime  importance.     Absolute  dry- 


OLIVERS  HEMATOCYTOMETER. 


35 


Fig. 


ness  of  tube  and  bulb  is  essential.  The  collection  of  minute  water 
drops  in  the  tube  and  bulb  is  responsible  for  many  of  the  shadow  cor- 
])nscles  sometimes  seen  in  the  counting-chamber. 

Every  few  weeks  a  pipette  should  be  cleaned  out  with  concentrated 
nitric  acid. 

(/)  Cleaning  the  Apparatus. — After  using  the  pipette,  the  rubber 
tube  may  be  transferred  to  the  long  arm  and  the  remaining  fluid  ex- 
pelled. The  tube  should  then  be  cleaned  thoroughly  with  water,  then 
with  alcohol  and  ether,  or  better,  with  pure  ether.  It  must  be  thor- 
oughly dried  before  using  again.  The  counting-chamber  must  be 
cleaned  with  water  only,  as  alcohol 
and  ether'  dissolve  the  cement  under 
the  shelf  and  plate. 

( g)  The  Limit  of  Error  with  the 
Hematocytometer. — Lyon,  Thoma, 
(and  Reinert),  counting  an  average 
of  1,141  cells  in  100  squares,  with 
a  dilution  of  1-200,  found  an  aver- 
age error  of  1.82  percent  in  24 
preparations  of  the  same  specimen, 
and  in  another  case,  counting  an 
average  of  934  cells  in  1 00  squares, 
1-200  dilution,  an  average  varia- 
tion of  2.71  percent,  in  12  prep- 
arations of  the  same  specimen. 
(Limbeck.)  These  results  in  the 
hands  of  experts  using  special  care, 
indicate  that  a  variation  of  150,- 
000  cells  (3  percent)  cannot  be  ac- 
cepted as  of  any  significance.  More 
accurate  data  are,  however,  seldom 
required  by  the  clinician. 

Oliver's  Hematocytometer. 
The  Principle. — When  a  candle 
flame  is  viewed  through  a  flat  glass 
tube  containing  water  a  transverse 
line  of  bright  light  is  seen  which 
results  from  the  blending  of  numerous  images  of  the  flame.  The  im- 
ages are  produced  by  the  minute  longitudinal  corrugations  in  the  glass 
which  reflect  the  light  in  various  directions.  When  diluted  blood  is 
placed  in  the  tube  the  fluid  is  sufficiently  opaque  to  shutout  the  images 
until  a  certain  dilution  is  reached  when  a  bright  streak  of  light  becomes 
rather  suddenly  visible. 

Oliver  believes  that  the  appearance  of  this  bright  horizontal  line  is 
a  very  sensitive  indicator  of  the  proportion  of  red  cells  in  the  fluid, 
and  by  a  long  series  of  observations  has  devised  an  instrument 
for  determining  the  number  of  red  cells  in  blood  according  to  this 
principle. 


Oliver's  hematocytometer.  A,  measuring 
pipette;  B,  dropper;  C,  mixing  tube  graduated 
iu  percentages ;    I),  mode  of  observation. 


36  GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 

The  apparatus  consists  of  a  measuring  pipette  (A) ;  a  dropper  for 
Havem's  fluid  (B) ;  a  flat  glass  tube  graduated  in  120  degrees  (C). 

The  Procedure. — The  capillary  pipette  is  carefully  filled  with 
blood  and  washed  into  the  tube  by  means  of  Hayem's  fluid.  A  proper 
amount  of  fluid  is  then  added  to  the  diluted  blood  and  the  two  are 
mixed  by  inverting  the  tube  closed  by  the  thumb,  care  being  taken 
not  to  remove  any  diluted  blood  with  the  thumb.  The  test  should  be 
made  in  a  dark  room,  the  light  being  furnished  by  a  Christmas  candle 
placed  about  ten  feet  from  the  operator.  When  the  blood  is  insuf- 
ficiently diluted  the  image  of  the  candle  is  invisible  when  looking 
through  the  tube  held  horizontally,  Fig.  7,  D,  but  at  a  certain  dilution 
the  images  begin  to  appear,  and  at  the  proper  dilution  a  rather  com- 
pact transverse  line  of  light  becomes  visible.  The  bottom  of  the  men- 
iscus is  then  read  off  on  the  graduated  scale.  Each  degree  of  the  scale 
represents  100,000  red  cells,  the  mark  100  corresponding  to  5  million 
cells,  80  to  4  million,  60  to  3  million,  etc. 

There  are  both  theoretical  and  practical  objections  to  the  use  of 
Oliver's  instrument.  Theoretically,  the  method  falls  in  the  undesir- 
able class  of  indirect  methods  about  which  there  are  always  a  large 
series  of  unknown  disturbing  factors,  which  can  only  be  eliminated  by 
prolonged  experience. 

Practically  the  difliculty  of  determining  the  exact  dilution  from  the 
appearance  of  a  compact  line  of  light  is  very  great.  The  method  can- 
not be  recommended  until  it  has  received  much  wider  application  than 
it  has  yet  enjoyed. 

The  Estimation  of  Leucocytes. 

The  leucocytes  may  be  counted  by  a  method  which  requires  a  spe- 
cial mixing  pipette,  yielding  a  dilution  of  blood  in  the  proportion  of 
1  to  10,  and  a  diluting  fluid  (3-percent  acetic  acid,  tinged  with  gen- 
tian violet)  which  dissolves  the  red  cells,  leaving  only  the  stained  leu- 
cocytes to  be  counted.  The  same  chamber  is  used  as  for  counting  red 
cells,  and  the  same  procedure  is  followed.  All  the  leucocytes  in  one 
square  millimeter  having  been  counted,  the  result  is  multiplied  by  100, 
giving  the  number  of  leucocytes  per  cubic  millimeter. 

The  disadvantages  early  recognized  in  this  method  are  the  expense 
and  inconvenieuce  of  an  extra  pipette,  and  a  second  diluting  fluid,  the 
time  required  in  preparing  a  second  specimen,  the  larger  quantity  of 
blood  required,  the  difficulty  sometimes  encountered  in  distinguishing 
leucocytes  from  the  detritus  of  red  cells,  and  the  impossibility  of  sep- 
arating and  evenly  distributing  the  cohesive  leucocytes. 

This  method  has  gradually  been  replaced  to  a  large  extent  by  the 
practice  of  counting  leucocytes  in  the  same  specirnen  prepared  for 
counting  the  red  cells.  In  1892  the  writer  found  that  he  secured 
more  uniform  results  with  the  latter  method,  and  has  since  found  no 
inducement  to  return  to  the  former. 

The  Counting  of  Leucocytes  in  the  Same  Preparation  with  the 
Red. — This  method  requires  the  Zappert  Chamber  which  was  orig- 


THE  ESTIMATION  OF  LEUCOCYTES. 


37 


inally  devised  by  Elsholz  for  the  estimation  of  eosinophile  cells  in 
fresh  blood.  Various  modifications  of  the  ruling  in  this  chamber 
liave  been  employed,  one  of  which,  made  by  Leitz,  at  the  writer's 
suggestion,  is  represented  in  Fig.  8. 

With  this  chamber  using  a  Leitz  lens.  No.  7,  it  is  possible  to  count 
over  nine  square  millimeters  which  gives  almost  as  many  leucocytes 
as  are  counted  in  the  other  method.  When  the  leucocytes  are  nor- 
mal or  reduced   in  number,  it  is  necessary  to  count  all  there   are   in 


Fig.  8. 


Palling  of  the  Zappert  chamber. 

the  available  9  sq.  mm.,  and  if  the  number  is  very  low  it  is  advisable 
to  prepare  a  second  specimen  in  the  chamber  and  count  the  white  cells 
in  18  sq.  mm.  When  the  leucocytes  are  increased,  9  sq.  mm.,  or  in 
cases  of  leukemia,  6  sq.  mm.,  will  yield  a  number  large  enough  to  in- 
sure an  accurate  result. 

In  order  to  make  the  leucocytes  visible  the  Toisson's  fluid  or  other 
solution  should  contain  enough  methyl-violet  to  stain  these  cells  dis- 
tinctly. With  a  little  practice  the  eye  picks  out  the  bluish  highly 
refractive  leucocytes  very  readily. 


38  GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 

What  has  been  said  regarding  the  condition  of  the  local  circulation,  and 
the  effects  of  pressure  in  expressing  the  blood,  is  to  be  specially  empha- 
sized when  estimating  the  number  of  leucocytes  in  a  specimen  of  blood. 

Computation. — Divide  the  number  of  leucocytes  counted  by  the 
number  of  square  millimeters  traversed  in  the  count  and  multiply  by 

I  000.     The  result  is  the  number  of  leucocytes  per  cubic  millimeter 
of  blood. 

If  the  original  dilution  is  1  to  200,  which  ought  not  to  be  employed 
except  in  cases  of  leukemia,  the  multiplier  is  2,000.  Thus  if  54 
leucocytes  are  counted  in  9  sq.  mm.  (dilution  1-100)  the  number  per 
cubic  mm.  is  6,000  (54  ^  9  x  1,000). 

The  Enumeration  of  Eosinophile  Leucocytes,  (a)  In  the  same 
Preparation  with  the  Red  Cells. — When  the  blood  is  diluted,  1-100, 
with  .6-percent  salt  solution  tinged  with  gentian  violet,  the  leuco- 
cytes retain  their  natural  size  and  shape  and  eosinophile  cells  can  be 
readily  identified  by  their  large,  greenish,  refractive  granules.  In 
cases  of  myelogenous  leukemia  this  method  is  satisfactory,  but  when 
the  eosins  are  present  in  their  usual  numbers  (1—5  percent)  one  must 
count  a  larger  number  than  can  be  found  by  this  method.  The  usual 
expedient  is  to  estimate  their  percentage  from  a  dried  specimen  of 
blood,  and  then  to  calculate  their  number  from  the  total  number  of  all 
leucocytes  counted  by  other  methods.  Thus,  if  the  count  shows 
12,000  leucocytes  per  cubic  mm.  and  the  dried  blood  slide  shows  2  per- 
cent of  eosins  their  number  will  be  240  per  cubic  millimeter. 

This  method  is  sufficiently  accurate  for  clinical  purposes. 

(6)  By  Means  of  Thoma's  Special  Pipette  for  the  Enumeration  of  Leu- 
cocytes.— Klein,  Mueller  and  Reider,  and  Elsholz  have  employed 
methods  for  the  accurate  estimate  of  eosins  adapted  to  finer  clinical 
work  and  to  experimental  research.  They  use  the  large  pipette  of 
Thoma  which  gives  a  dilution  of  1-10.  The  capillary  tube  is  filled 
with  blood  to  the  mark  1,  and  the  bulb  is  half  filled  with  the  following 
solution  :  Watery  eosin  (2  percent),  7  parts  ;  glycerine,  45—  ;  Aq. 
dest.,  55  —  .     After  shaking  3-4  minutes  the  bulb  is  filled  to  the  mark 

II  with  the  following  staining  fluid  :   Aq.  dest.,  15  cc;  gentian  violet, 
cone.  aq.  sol.  5  drops,  alcohol  1  drop. 

In  specimens  thus  prepared  both  neutrophile  and  eosinophile  leuco- 
cytes are  readily  distinguished,  the  eosins  being  particularly  brilliant. 
The  red  cells  are  dissolved  and  the  leucocytes  concentrated  so  that  a 
sufficient  number  of  eosins  may  be  counted. 

Zappert's  extensive  studies  of  eosinophile  leucocytes  were  conducted 
with  specimens  diluted  in  the  large  pipette  of  Thoma,  by  the  following 
solution  :  1 -percent  osmic  acid  sol.,  5  cc,  to  which  are  added  5  drops  of 
a  filtered  mixture — Aq.  dest.  10  cc,  glycerine,  10  cc,  1-percent  watery 
eosin,  5  cc. 

THE    ESTIMATION    OF    HEMOGLOBIN. 

1.  Gower's  Hemoglobinometer. — This  instrument  has  always  been 
largely  employed  on  account  of  its  cheapness  and  simplicity,  and  the 


THE  ESTIMATION  OF  LEUCOCYTES. 


39 


Fig.  9. 


ease  and  rapidity  with  which  its  results  are  obtained.  Except  with 
low  percentage  of  Hb,  it  is  tolerably  accurate,  but  much  less  reliable 
than  Fleischl's  instrument.  With  low  percentages  of  Hb  it  is  well  to 
use  a  double  quantity  of  blood,  halving  the  result. 

Aside  from  any  inaccuracy  in  the  construction  of  the  apparatus, 
errors  arise  chiefly  from  the  difficulty  of  adding  exactly  the  proper 
quantity  of  water  to  the  blood,  and  the  imperfect  comparison  of  red 
eolors  in  daylight.  The  apparatus  consists  of  two  glass  tubes  (A,  B) 
of  exactly  equal  caliber,  one  of  which  is  partly  filled  with  gelatine  col- 
ored by  picrocarmine  so  as  to  represent  the  color  of  a  1 -percent  solu- 
tion of  normal  blood.  The 
second  tube  carries  a  grad- 
uated scale  from  10  to  120 
and  serves  to  hold  the  di- 
luted blood.  The  capil- 
lary pipette  C  measures 
20  cmm.,  the  quantity  of 
blood  to  be  used. 

In  making  the  test  the 
pipette  is  filled  to  the  mark 
20  cmm.  with  blood  ob- 
tained under  the  usual  pre- 
cautions. The  specimen 
is  quickly  discharged  into 
the  tube  B,  in  which  a 
few  drops  of  distilled 
water  have  previously 
been  placed.  The  pipette 
must  then  be  washed  once 
or  twice  into  the  tube,  the 
distilled  water  removing 
all  traces  of  blood  adher- 
ent to  the  inside  of  the 
capillary  tube.  Distilled 
water  is  now  added  drop 
by  drop,  until  the  solution  of  blood,  carefully  shaken  and  mixed,  ex- 
actly matches  the  carmine-gelatine.  The  percentage  of  Hb  is  indicated 
by  the  height  of  the  solution  on  the  scale,  reading  from  the  middle  of 
the  meniscus.  The  colors  match  in  daylight,  and  the  eye  may  be  as- 
sisted by  holding  the  tube  in  front  of  white  paper. 

2.  Fleischl's  Hemoglobinometer.  («)  Apparatus. — This  apparatus 
consists  of  a  metal  stand  with  plate  and  plaster  mirror,  8,  which  casts 
diffused  light  through  a  circular  opening  in  the  plate.  Beneath  the 
plate,  by  means  of  a  rack  and  wheel  {T),  slides  a  colored  glass 
wedge  fixed  in  a  graduated  frame,  P.  The  glass  wedge  and  graduated 
scale  are  arranged  so  as  to  indicate  the  percentage  of  Hb  correspond- 
ing to  the  different  portions  of  the  wedge.  In  the  circular  opening  of 
the  plate  fits  a  cylindrical  metallic  cell  ((r),  with  glass  bottom  and 


Gower's  hemoglobinometer. 


40 


GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 


ii 


metal  partition,  one  compartment  of  which  lies  directly  over  the  glass 
wedge.  The  other  compartment  {a)  being  filled  with  diluted  blood, 
one  is  enabled  to  make  a  close  comparison  of  the  color  of  the  dissolved 
blood  with  that  of  the  glass  wedge.  The  blood  is  measured  by  an  au- 
tomatic capillary  pipette,  while  a  slowly  running  dropper  is  provided 
with  which  to  add  distilled  water.  On  the  handle  of  each  pipette  is 
stamped  a  number,  indicating  the  cubic  content  of  the  tube.  On  the 
stand  of  each  instrument  is  also  a  number,  showing  the  capacity  of  the 
tubes  Avith  which  it  can  be  used. 

(6)  Procedure. — One  should  first  see  that  the  automatic  pipette 
is  in  working  order,  by  blowing  it  out  several  times  with  water  until 
it  fills  instantly  and  completely,  after  which  it  must  be  thoroughly 
dried.  A  drop  of  blood  having  been  expressed  under  very  strict  pre- 
cautions against  pressure,  one  end  of  the  pipette  is  lightly  touched  to 
the  drop  wliich  instantly  fills  the  tube.  There  should  be  neither  nega- 
tive nor  positive  meniscus  to  the  column  of  blood,  but  the  tube  should 
be  level  full  at  either  end.  It  should  not  be  immersed  in  the  blood 
drop,  otherwise  blood  will  adhere  to  the  sides  which  cannot  safely  be 
removed.  The  tube  of  blood  is  immediately  transferred  to  one  com- 
partment of  the  cell  which  has  been  half  filled  with  distilled  water,  and 

the  blood  is   thoroughly 
Fig.  10.  dissolved  by  moving  the 

tube  rapidly  from  side  to 
side.  On  withdrawing 
the  tube  it  should  be 
washed  into  the  cell  with 
a  few  drops  of  distilled 
water.  With  the  handle 
of  the  pipette  the  blood 
which  collects  in  the  cor- 
ners of  the  chamber  is 
thoroughly  mixed.  Both 
chambers  of  the  cell  may 
now  be  filled  level  full 
with  water.  The  thick 
round  cover-glass  should 
then  be  adjusted,  avoid- 
ing the  inclosure  of  air. 
Serious  error  may  here 
result  by  forcing  dis- 
solved blood  over  into 
the  water  compartment, 
or  over  the  side  of  the  cell.  If  the  reading  is  made  promptly  the 
cover-glass  need  not  be  used,  but  after  an  exposure  of  10-15  minutes 
the  oxidizing  action  of  the  air  may  darken  the  blood  and  increase  the 
reading  10-15  percent. 

The  reading  must  be  done  in  a  dark  room  by  means  of  candle- 
or  gaslight.     The  colors  do  not  match  in  daylight.     The  best  results 


Fleischl's  hemoglobinometer. 


THE  ESTIMATION  OF  HEMOGLOBIN.  41 

are  obtained  by  placing  the  candle  about  eighteen  inches  from  the 
stand,  and  by  looking  through  an  improvized  paper  tube  which  ex- 
actly fits  the  cell.  With  low  percentages  of  Hb  a  very  dim  light  is 
essential.  When  the  cell  is  in  place,  and  the  light  adjusted,  the 
wedge  is  moved  with  quick  rather  than  gradual  turns  until  the  color 
of  the  glass  exactly  matches  that  of  the  dissolved  blood,  when  the 
percentage  of  Hb  may  be  read  on  the  scale.  Several  expedients  are 
employed  to  assist  the  eye  in  the  comparison  of  colors.  It  is  well 
to  relieve  one  eye  with  the  other  so  as  not  to  exhaust  the  color  sense. 
The  strength  of  the  light  may  be  varied  by  altering  its  distance,  but 
the  faintest  distinct  light  is  usually  found  to  be  the  best.  Two  or 
three  readings  should  always  be  made  and  the  average  taken.  As  the 
graduation  of  the  instrument  is  more  accurate  and  the  matching  of 
colors  more  exact  in  the  middle  of  the  scale,  it  is  advisable  to  use  a 
double  quantity  of  blood  when  dealing  with  low  percentages  of  Hb. 

(c)  Limitations  of  Fleischl's  Instrument. — With  considerable  experi- 
ence and  constant  care  Fleischl's  instrument  yields  results  which  are 
sufficiently  accurate  for  most  clinical  purposes.  One  cannot  attach 
any  significance,  however,  to  a  variation  of  five  percent,  within  which 
figure  the  ordinary  error  ought  to  be  limited. 

All  the  causes  of  error  mentioned  as  affecting  the  number  of  red 
cells  may  also  disturb  the  percentage  of  Hb  in  the  blood  drop.  In 
the  procedure  the  principal  difficulties  relate  to  the  even  filling  of  the 
tube,  the  thorough  cleaning  of  the  tube,  the  overflow  of  blood  solu- 
tion into  the  adjoining  chamber,  the  proper  adjustment  and  regulation 
of  the  light,  and  the  accurate  matching  of  colors. 

The  chief  sources  of  error  in  this  method  probably  lie  in  the  con- 
struction of  the  instrument.  It  is  a  common  experience  to  find  that 
different  instruments  give  different  results  with  the  same  specimen  of 
blood,  which  Limbeck  satisfied  himself  were  referable  principally  to 
differences  in  the  glass  wedges. 

The  writer  tested  his  own  blood  with  16  different  instruments,  two 
of  which  were  old  (1892),  the  others  of  more  recent  importation 
(1897).  With  the  two  old  instruments  the  Hb  registered  87  percent 
and  90  percent;  with  the  newer  instruments  it  varied  between  97 
percent  and  105  percent,  except  with  one  which  gave  85  percent 
with  different  cells  and  different  capillary  tubes.  The  colored  wedge 
with  this  instrument  was  broader  and  darker  than  usual,  and  when  it 
was  replaced  by  another  wedge  the  instrument  registered  100  per- 
cent with  the  same  specimen.  The  error  attributable  to  variations  in 
different  tubes  and  cells  the  writer  finds  is  seldom  greater  than  five  per- 
cent among  the  newer  instruments.  Many  old  instruments  read  10—15 
percent  lower  than  normal. 

The  possible  combination  of  these  various  defects  in  construction 
renders  it  desirable  that  one  should  test  every  new  instrument  for  him- 
self using  the  blood  of  five  or  six  healthy  subjects.  The  newer  in- 
struments will  not  be  found  to  require  much  correction. 

Miescher's    Modification    of    Fleischl's    Hemoglobinometer. — 


42 


GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 


Miescher's  improvements  have  removed  some  important  defects  in 
Fleischl's  instrument,  and  as  it  now  stands  the  improved  hemoglobin- 
ometer  yields  results  that  leave  little  to  be  desired  in  point  of  accuracy. 

With  this  apparatus  the  blood  is  diluted  by  means  of  a  graduated 
pipette  very  similar  to  that  of  Thoma,  but  yielding  dilntions  of  1-200, 
1-300,  and  1-400,  according  as  the  tube  is  filled  with  blood  to  the 
mark  i,  |,  or  ^. 

Two  cells  are  provided,  one  with  a  depth  of  15  mm.,  the  other  with 
a  depth  of  12  mm.,  the  percentage  of  Hb  being  obtained  with  the 
deeper  cell,  and  the  other  being  used  as  a  control  specimen  and  giving 
only  I  (i|)  of  the  actual  percentage  of  Hb. 

These  cells  have  a  projecting  jpartition  dividing  the  compartments, 


Miescher's  hemoglobinometer. 

along  which  a  grooved  cover-glass,  D,  may  be  slid,  without  fear  of  mix- 
ing the  blood  and  water.  If  an  excess  of  the  blood  solution  overflows 
the  side  of  the  cell  during  the  adjustment  of  the  cover,  no  harm  results 
as  the  blood  is  already  properly  diluted  in  the  pipette,  and  the  depth 
in  the  chamber  will  always  be  15  mm.  (or  12).  These  changes  add 
very  much  to  the  facility  and  precision  of  the  method. 

Finally,  the  cells  are  covered  with  diaphragms  transmitting  a  ray  of 
light  which  includes  only  three  degrees  on  the  scale,  thus  giving  prac- 
tically a  single  color  of  the  wedge  for  comparison  with  the  blood. 

In  the  procedure,  the  blood  is  diluted  in  the  pipette  as  with  the 
hematocytometer,  the  diluting  fluid  being  distilled  water,  or  a  filtered  1- 
percent  solution  of  sodium  carbonate.  After  shaking  and  clearing  the 
tube  of  diluent,  one  chamber  in  each  cell  is  filled  with  diluted  blood. 


OLIVER'S  HEMOGLOBINOMETER.  43 

the  opposite  chamber  with  distilled  water,  and  cover-glasses  and  dia- 
phragms are  adjusted.  Using  a  small  candle  and  shielding  the  eyes 
from  light,  the  readings  with  the  two  cells  are  carefully  taken.  The 
reading  with  the  small  cell  should  be  ^  that  with  the  larger.  If  there 
is  any  variation  one  reading  may  be  used  to  correct  the  other.  For 
example,  suppose  the  readings  to  be  : 

For  the  larger  chamber  (15  mm.) 64.0 

For  the  smaller  chamber  (12  mm.) 50. 

If  the  first  reading  were  absolutely  correct  the  second  reading  should 
have  been  51.2,  since  64  x  |-  =  51.2.  Or,  assuming  the  second  to 
be  correct,  the  first  should  have  been  62.5,  since  50  x  f  =  62.5.  The 
mean  of  64  and  62.5,  i.  e.,  63.25,  should  be  taken  as  the  true  value. 

If  the  original  dilution  \Vas  1-200,  the  percentage  of  Hb  is  63.25, 
the  corrected  result  with  the  larger  cell,  but  if  the  dilution  has  been 
1-300,  this  result  must  be  multiplied  by  Ih,  or  if  1-400,  by  2. 

The  technical  difficulties  of  this  method  are  so  slight  and  the  results 
so  accurate  that  the  instrument  may  be  recommended  over  any  other 
yet  devised  for  this  purpose. 

Oliver's  Hemoglobinometer. — This  instrument  is  constructed  on 
the  excellent  principle  of  the  tintometer,  which  is  extensively  used  in 
various  arts  and  industries. 

It  consists  of  a  series  of  six  red  glass  discs,  («),  mounted  upon  white 
plaster  mirrors  in  convenient  frames.  These  discs  represent  the  colors 
of  twelve  solutions  of  blood  containing  twelve  different  proportions  of 
Hb.  Two  sets  of  discs  are  made,  one  for  reading  in  daylight,  the 
other  for  candlelight.  The  latter  give  more  accurate  results  and 
should  be  chosen.  The  intermediate  percentages  of  Hb  are  secured 
by  means  of  ''  riders  "  of  colored  glass  to  be  placed  over  the  discs,  and 
which  represent  respectively  2|^  and  5  percent  of  Hb  in  the  upper 
half  of  the  scale,  but  twice  that  amount  in  the  lower  half.  The  discs 
are  graded  according  to  the  specific  dilution-curve  of  Hb. 

The  blood  is  measured  in  an  automatic  pipette,  c,  and  diluted  in  a 
cell,  e,  provided  with  a  white,  plaster,  glass-covered  bottom,  and  blue 
glass  cover,  which  facilitates  the  reading.  The  blood  is  washed  from 
the  tube  by  means  of  a  pipette,  d,  with  rubber  nozzle.  The  tube  may 
be  cleaned  by  means  of  a  thread  and  needle. 

Procedure. — The  capillary  tube  is  filled  by  touching  it  to  the  blood- 
drop,  and  the  blood  is  washed  into  the  cell  by  attaching  the  rubber 
nozzle  of  the  pipette,  filled  with  distilled  water,  taking  care  not  to  as- 
pirate any  blood  into  the  pipette.  The  handle  of  the  tube  is  then  used 
to  mix  the  blood,  and  water  is  carefully  added  till  the  cell  is  level  full. 
The  cover  is  then  applied  and  should  inclose  a  minute  air  bubble  show- 
ing that  the  chamber  has  not  been  overfilled.  The  comparison  of 
colors  should  be  made  by  candlelight,  the  candle  being  placed  at  a 
convenient  distance  from  the  discs,  and  the  eye  shielded  by  means  of  a 
hood  or  paper  tube.  Oliver  uses  a  special  camera  with  green-glass 
eye-piece.  If  the  color  of  the  specimen  matches  any  one  of  the  discs  the 
reading  is  completed.    If  it  does  not,  the  discs  may  be  varied  by  using  the 


44 


GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 


"  riders,"  adding  a  clear  glass  disc  to  the  specimen  to  compensate  for 
the  thickness  of  the  "  rider." 

Oliver's  instrument  presents  the  advantage  of  a  comparison  with  a 


Fio.  12. 


Oliver's  hemoglobinometer :    a,  set  of  standard  colored  discs  ;  b,  lancet ;  c,  capillary 
pipette  ;  d,  dropper  ;    e,  mixing  chamber. 

^ngle  color  instead  of  with  a  scale  of  10  percent  +,  as  in  Fleischrs. 
ihis  difficulty  is  slight,  however,  and  is  overcome  in  Miescher's  modi- 
hcation  of  Fleischl's  instrument.     The  color  of  FleischPs  glass  wedge 


ESTIMATION  OF  THE  IRON  OF  THE  BLOOD. 


45 


varies  accordiDg  to  the  specific  dilution-curve  of  the  colored  glass, 
which  differs  from  the  specific  dilution-curve  of  Hb.  How  serious  an 
error  may  arise  with  Fleischl's  instrument  from  this  cause  has  not  been 
clearly  shown.  It  is  probably  not  great,  as  it  is  not  apparent  in  the 
use  of  Miescher's  modification  in  which  different  parts  of  the  scale  are 
employed.  Yet  the  principle  of  Oliver's  instrument  is,  in  this  respect, 
a  distinct  improvement.  The  technical  difficulties  are  considerably 
less  with  Miescher's  hemoglobinometer.  Oliver's  instrument  is  at 
present  held  out  of  the  market  on  account  of  its  excessive  price. 

Estimation  of  the  Iron  of  the  Blood.  Jolles'  Ferrometer. — JoUes 
has  devised  a  method  and  designed  apparatus  for  the  estimation  of  the 
iron  of  the  blood,  which  is  well  adapted  to  clinical  purposes. 

The  apparatus  is  manufactured  by  Reichert,  and  full  directions  in 
German  accompany  each  set. 

The  procedure  is  as  follows  : 

By  means  of  a  pipette  .05  cc.  of  blood  is  transferred  to  a  platinum 
crucible,  and  the  adherent  blood  washed  out  with  a  few  drops  of 
water.     The  blood  is  then  evaporated  and  incinerated  over  a  Bunsen 

Fig.  13. 


Jolles'  ferrometer. 


flame.  The  ash  is  melted  with  .1  gr.  water-free  potassium  bisulphate, 
until  white  fumes  of  sulphuric  anhydride  cease  to  rise  from  the  dish. 

Papers  containing  the  requisite  amount  of  potassium  bisulphate 
accompany  the  instrument.  After  cooling,  the  ash  is  washed  into  cyl- 
inder C  (Fig.  14)  with  about  5  cc.  of  hot  distilled  water  which  is 
added  till  the  whole  quantity  is  10  cc. 

In  cylinder  C,  1  cc.  of  the  standard  solution  of  iron  (.00005  gr. 
iron  oxide  with  potassium  sulphate)  is  measured  by  a  pipette  and 
distilled  water  added  to  the  mark  10  cc.      Both  cylinders  are  now 


46 


GENERAL  PHYSIOLOGY  AND  PATHOLOGY 


placed  in  the  stand  (Fig.  14),  and  when  at  even   temperature  1  cc.  of 
dihite  HCl  (33  percent)  is  added  to  each. 

To  cylinder  C'  should  then  be  added  4  cc.  of  the  solution  of  am- 
monium sulphocyanide,  and  to  cylinder  C,  about  3.5  cc,  and  both 
are  shaken  after  covering  the  ends  with  glass  plates. 

Cylinder  C  containing  the  blood  is  now  filled  with  sulphocyanide 
until  it  presents  a  positive  meniscus  when  it  is  permanently  covered 
and  sealed  by  its  glass  plate.  It  may  then  be  placed  in  the  colorim- 
eter. In  cylinder  C  the  aluminum  float  is  then  adjusted,  free  from 
air  bubbles,  and  it  is  also  placed  in  position  in  the  colorimeter. 

The  further  procedure  consists  in  bringing  the  color  of  C"  to  match 
that  in  C,  when  viewed  from  above  in  the  colorimeter.      For  this  pur- 
pose the  fluid  in  C  is  allowed  to  run  out  drop  by  drop  through  a  stop- 
cock until  the  two  colors  are  exactly 
Fig.  U.  alike.     The  comparison  should    be 

made  in  daylight.  When  the  colors 
exactly  match,  the  height  of  the 
necessary  column  of  fluid  in  cylinder 
C  may  be  read  off  and  the  per- 
centage weight  of  iron  determined 
by  reference  to  a  table  accompany- 
ing the  instrument.  The  Hb  may 
then  be  found  according  to  v.  Jak- 
sch's  formula. 


Hb  = 


100  X  m 
.42 


in  which  la  =  the  percentage  weight 
of  metallic  iron. 

In  order  to  secure  accurate  results 
with  the  ferrometer  it  is  necessary 
to  observe  the  same  care  that  is  re- 
quired in  all  quantitative  chemical 
joUes'  ferrometer.  aualyscs,  cspccially  to  avoid  the  loss 

of  fluids  by  sputtering  from  the 
hot  crucible,  the  use  of  wet  and  unclean  instruments,  and  the  inclos- 
ure  of  air  bubbles,  etc.  Under  most  conditions  the  Hb  may  be  accu- 
rately determined  by  means  of  the  above  formula,  but  from  the  consid- 
erations mentioned  under  "  The  occurrence  of  iron  in  the  blood,"  it 
will  be  seen  that  there*  may  be  considerable  variations  between  the  iron 
and  the  Hb-content.  The  ferrometer,  therefore,  usually  gives  a  higher 
proportion  of  Hb  than  does  Fleischl's  instrument. 

THE    HISTOLOGICAL    EXAMINATION    OF    BLOOD. 

The  greater  part  of  the  examination  of  blood  is  conducted  in  dry 
stamed  specimens.     To  prepare  such  specimens  for  staining  one  re- 


THE  HISTOLOGICAL  EXAMINATION  OF  BLOOD.  47 

quires  only  polished  glass  slides  aud  a  Buiisen  gas-burner.  The  glass 
slides  must  be  thoroughly  cleaned  with  soap  and  water,  dried,  and 
kept  free  from  dust. 

A  rather  small  compact  drop  of  blood  expressed  from  the  finger  tip 
under  the  usual  precautions,  is  lightly  scraped  off  with  the  polished 
edge  of  one  slide  and  applied  to  one  end  of  a  second  slide  which 
should  lie  on  firm  support.  When  the  blood  has  spread  along  the 
edge  of  the  smearer  it  should  be  slowly  and  firmly  drawn  over  the 
surface  of  the  receiving  slide.  The  drop  should,  if  possible,  be  small 
enough  to  be  exhausted  in  the  smearing,  and  the  thickness  of  the  layer 
can  be  fully  controlled  by  the  degree  of  pressure.  The  blood  should 
be  pushed  before  the  smearer  and  not  trailed  after.     (See  sketch.) 

Many  prefer  to  use  cover-glasses  in  spreading  the  blood.  One 
polished  cover-glass  is  touched  to  the  drop  of  blood  and  applied  to  a 
second  cover,  all  corners  projecting.  When  the  blood  has  spread  to 
the  edges  the   cover-glasses  are  gently  slid  apart  without  pressure. 

Fig.  15. 


Method  of  making  blood  smears. 

The  cover-glasses  should  be  handled  with  forceps,  otherwise  the  mois- 
ture of  the  finger  will  often  crenate  many  cells. 

The  writer  prefers  to  use  glass  slides,  finding  that  beginners  are 
much  more  successful  with  the  slides  than  with  cover-glasses,  that, 
after  very  little  practice,  eveiy  specimen  can  be  spread  successfully  ; 
that  forceps  are  not  required  ;  that  slides  may  be  handled  and  trans- 
ported without  fear  of  breakage  ;  that  they  need  not  be  mounted  and 
therefore  do  not  fade  like  cover-glass  specimens  which  require  mount- 
ing in  balsam  ;  that  they  may  be  restained,  if  necessary  ;  and  above 
all  that  they  may  safely  be  fixed  in  the  free  flame. 

After  spreading,  all  specimens  should  be  well  dried  in  the  air.  They 
may  then  be  kept  for  weeks  if  wrapped  in  tissue  paper  and  kept  from 
moisture,  but  it  is  better  io  fix  them  at  once. 

Fixation.  1.  Heat. — In  routine  work  one  may  discard  all  other 
methods  for  that  of  fixation  in  the  free  fiame  of  a  Bunsen  burner.  The 
slide,  specimen  side  up,  is  passed  slowly  through  the  flame  until  it  is 


48  GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 

decidedly  too  hot  for  the  hand  to  bear.  At  this  temperature,  which 
probably  varies  between  110°  and  150°  C.  fixation  is  complete  in  one 
to  two  minutes. 

A  little  practice  will  give  the  confidence  necessary  to  heat  the  slides 
hot  enouo-h,  as  one's  initial  failures  from  this  method  almost  always 
result  from  incomplete  fixation  and  subsequent  vacuolization  of  the 
red  cells.  Overheated  slides  can  usually  be  seen  to  change  color  in 
the  flame,  after  which  the  red  cells  stain  yellowish  with  eosin.  The 
beginner  is  strongly  recommended  to  perfect  himself  in  this  simple 
method  of  fixation. 

Small  ovens,  provided  with  a  thermometer,  are  made  for  the  fixation 
of  blood  slides,  and  may  be  used  when  many  specimens  are  in  hand, 
or  when  one  does  not  care  to  risk  the  free  flame.  Specimens  should 
be  exposed  5-10  minutes  to  a  temperature  of  110°-120°  C. 

2.  Alcohol. — Fixation  for  10-30  minutes  in  97-percent  alcohol,  or 
in  equal  parts  of  alcohol  and  ether,  is  a  very  reliable  method,  in  very 
general  use.  Specimens  may  be  left  in  alcohol  for  twenty-four  hours, 
but  do  not  then  stain  quite  so  well.  There  appears  to  be  no  advantage 
in  adding  ether  to  the  alcohol,  which  even  without  mixture  with  the 
more  volatile  agent  must  frequently  be  replaced.  Fixation  in  alcohol 
is  to  be  specially  recommended  for  the  malarial  parasite,  but  is  unsat- 
isfactory when  Ehrlich's  triacid  stain  is  to  be  used. 

3.  Fixation  by  Vapors. — Specimens  may  be  fixed  by  being  laid,  speci- 
men side  down,  over  a  wide-mouthed  bottle  containing  :  25-percent 
formalin,  to  which  the  exposure  is  five  minutes,  or,  2-percent  osmic 
acid,  to  which  expose  two  minutes.  Both  these  fluids  have  to  be  re- 
placed frequently,  they  considerably  alter  the  staining  relations  of  the 
blood  cells,  and  are  inferior  to  other  methods  of  fixation. 

Methods  of  Staining  Dry  Blood  Specimens.  1.  Eosin  and 
Methylene -blue. — The  solutions  required  are  :  A  saturated  alcoholic 
solution  of  Ehrlich's  blood-eosin.  A  saturated  watery  solution  (1-per- 
cent) of  Ehrlich's  rectified  methylene-blue.  The  latter  should  be  at 
least  one  week  old,  as  fresh  solutions  lack  selective  quality  and  stain 
the  specimen  diffusely.  After  several  weeks,  methylene-blue  in  solu- 
tion diminishes  in  staining  power,  while  the  alcoholic  eosin  absorbs 
water,  and  becomes  less  selective  and  more  powerful. 

In  staining,  flood  the  specimen  with  eosin  for  a  few  seconds  and 
wash  in  water.  If  the  stain  is  not  effective  add  more  eosin,  but  the 
water  on  the  slide  dilutes  the  alcohol  and  renders  the  second  applica- 
tion of  eosin  much  more  powerful  than  the  first.  Next,  flood  the 
specimen  repeatedly  for  one  minute  with  methylene-blue,  wash  hastily 
in  water,  and  dry. 

This  method  may  be  recommended  for  all  ordinary  examinations. 
The  blood  is  stained  as  shown  in  Plate  II.,  readily  distinguishing  the 
various  forms  of  normal  leucocytes.  It  does  not  stain  neutrophile 
granules  in  leucocytes  unless  the  action  of  eosin  has  been  prolonged, 
in  which  case  the  neutrophile  leucocytes  can  be  distinguished  from  the 
eosinophile  only  by  the  size  of  the  granules.     Its  chief  advantage  is 


ESTIMATION  OF  SPECIFIC  GRAVITY  OF  THE  BLOOD.         49 

the  clear  differentiation  of  basophilic  leucocytes  and  of  nuclear  struc- 
tures. It  clearly  demonstrates  the  malarial  parasite  but  in  this  field 
is  greatly  inferior  to  Nocht's  method.  Its  chief  disadvantage  is  the 
danger  of  overstaining  with  eosin  which  prevents  the  full  action  of 
methy  leue-bl  ue. 

2.  Ehrlich's  Triacid  Mixture. — This  agent  has  the  following  com- 
position : 

Sat.  watery  sol.,  Orange  G 120-135  cc. 

Acid  Fuchsine 80-165 

Methyl -green 125 

To  these  add        Aqua 300 

Absolute  alcohol 200 

Glycerine 100 

The  attempt  to  prepare  this  mixture  is  not  always  successful.  The 
smaller  quantities  of  orange  G,  and  acid  fuchsine  are  best  employed, 
and  the  solution  of  methyl-green,  well  seasoned,  should  be  added 
slowly,  with  stirring,  to  the  mixture  of  the  other  dyes.  The  water 
should  be  added  next,  then  the  alcohol,  and  finally  the  glycerin,  with 
constant  stirring.  After  standing  one  week  the  mixture  is  ready  for  use. 
Griibler's  preparation  of  this  mixture  is  in  the  market  and  is  reliable. 

In  staining,  it  is  only  necessary  to  flood  the  specimen  with  the  dye 
for  one  to  two  minutes,  and  wash  hastily  in  water.  It  cannot  over- 
stain,  but  overheated  specimens  are  usually  faint,  and  the  red  cells 
are  yellowish.  It  stains  neutrophile  and  eosinophile  granules  deep 
red,  the  latter  being  distinguished  by  their  size.  It  is  therefore  indis- 
pensable in  the  diagnosis  of  leukemia.  It  is  a  poor  nuclear  stain,  fails 
to  demonstrate  the  structure  of  normal  mononuclear  leucocytes,  and 
does  not  stain  the  malarial  parasite. 

On  account  of  the  uniformity  of  its  results  many  prefer  it  to  eosin 
and  methylene-blue  as  a  routine  method. 

3.  Demonstration  of  "  Mast-cells." — The  large  basophilic  granules 
of  these  cells  retain  basic  dyes  with  tenacity,  and  may  be  demonstrated 
by  a  mixture  of  one  of  these  dyes,  with  a  strong  decolorizer,  which 
removes  the  stain  from  most  other  basophile  structures.  Ehrlich's 
dahlia  solution  is  adapted  to  this  purpose  : 

Abs.  alcohol 50  cc. 

Glacial  acetic  acid 12.5  cc. 

Distilled  water 100.  cc. 

Add  dahlia  to  saturation. 

Stain  several  hours,  wash  in  water,  decolorize  in  alcohol  or  more 
rapidly  in  20-percent  Ac,  till  the  nuclei  fade,  and  wash  in  water. 
The  nuclei  of  leucocytes  are  then  very  pale  blue,  the  mast-cell  granules 
very  dark  blue  or  black. 

ESTIMATION    OF   THE   SPECIFIC   GRAVITY   OF    THE   BLOOD. 

Hammerschlag's  Method  is  the    most   practical   of  the   various 
indirect    procedures     devised    for    this    purpose.      A    small     urino- 
meter  of  suitable  dimensions  is  partly  filled  with  a  mixture  of  chloro- 
4 


50  GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 

form  (s.  g.  1.526)  and  benzine  (s.  g.  .889),  of  a  gravity  of  about  1.060. 
By  means  of  a  pipette,  such  as  the  red  cell  mixer  of  Thoma,  a  drop  of 
blood,  expressed  with  the  usual  precautions,  is  transferred  to  the  fluid. 
In  expelling  the  blood  the  tip  of  the  pipette  should  be  submerged 
and  no  air  should  be  allowed  to  pass  out  with  the  blood.  The  drop 
should  not  be  very  minute  in  size  and  should  float  on  the  fluid.  If  it 
is  allowed  to  sink,  it  will  often  be  lost  by  spreading  out  on  the  bottom 
of  the  vessel.  By  adding  chloroform  or  benzine,  drop  by  drop,  as 
required,  and  carefully  mixing  by  inverting  the  urinometer  closed  by 
the  palm,  a  mixture  is  secured  in  w^hich  the  drop  neither  rises  nor 
sinks,  but  which  is  of  exactly  the  same  density  as  the  blood.  The 
specific  gravity  of  the  mixture,  and  of  the  blood,  may  then  be  taken 
as  with  urine.  The  urinometer  should  be  graduated  up  to  1,065,  and 
should  be  tested  in  distilled  water  at  60°  F.  The  apparatus  should 
be  clean  and  perfectly  dry.  The  mixture  may  be  filtered  and  used 
repeatedly. 

Great  accuracy  can  hardly  be  expected  from  this  method  yet  it  is 
sufficiently  reliable  for  clinical  purposes.  Errors  arise  from  changes 
in  the  blood  drop  during  and  after  its  transfer  to  the  mixture,  from 
evaporation,  from  the  escape  of  gases,  from  the  inclosure  or  adherence 
of  minute  air  bubbles,  and  perhaps  also  from  the  possible  action  of 
chloroform  and  benzine  upon  the  blood  which  is  at  present  an  unknown 
factor.  Accordingly,  Hammerschlag's  method  gives  a  uniformly 
higher  gravity  than  is  obtained  by  more  accurate  direct  estimates. 
Practically,  in  performing  the  test  one  finds  that  the  behavior  of  the 
drops  varies,  for  reasons  which  are  not  clear,  some  rising  and  others 
falling  in  the  same  mixture.  A  large  drop  should  be  secured  and  fol- 
lowed in  the  test. 

Since  the  specific  gravity  of  the  blood  in  simple  anemia  varies 
principally  with  the  Hb,  the  percentage  of  Hb  may  in  many  cases  be 
calculated  with  considerable  accuracy  from  the  specific  gravity.  Ham- 
merschlag  has  prepared  the  following  table  showing  the  relation  of  Hb 
to  the  specific  gravity  as  determined  by  his  method  : 

Specific  Gravity.  Hb. 

1033-1035 25-30   percent. 

1035-1038 30  35  " 

1038-1040 35-40  " 

1040-1045 40-45  " 

1045-1048 .....45-55  " 

1048-1050 55-65  " 

1050-1053 65-70  " 

1053-1055 70-75  " 

1055-1057 75-85  " 

1057-1060 85-95  " 

The  suggestion  that  Fleischl's  hemoglobinometer  be  discarded  for  this 
indirect  method  of  estimating  Hb  has  not  found  favor.  The  changes 
in  the  plasma  in  severe  anemia,  leukemia,  dropsy,  and  diarrheal  dis- 
eases, renders  this  practice  always  unscientific  and  frequently  very  un- 
reliable.    (Cf.  Siegel,  and  Stintzing  and  Gumprecht.) 


ESTIMATION  OF  ALKALESCENCE  OF  THE  BLOOD.  51 

Schmaltz'  Method. — A  thin-walled  capillary  glass  tube  is  prepared, 
about  12  mm.  in  length,  aud  of  a  calibre  of  about  |  mm.  at  the  ends  and 
li  mm.  at  the  middle.  This  is  thoroughly  cleaned,  dried  and  weighed 
Ijefore  and  after  filling  with  distilled  water.  After  drying  with  ether 
the  tube  is  filled  with  blood  and  again  weighed.  The  weight  of  the 
lilood  divided  by  that  of  the  water  gives  the  specific  gravity  of  the 
former. 

Fig.  16. 


Capillary  glass  tube  adapted  to  various  details  of  blood  analysis. 

This  is  the  best  of  the  methods  requiring  a  small  quantity  of  blood, 
and  in  experienced  hands  gives  more  accurate  results  than  Hammer- 
schlag's  method.  It  is  to  be  especially  recommended  in  experimental 
and  laboratory  work,  but  usually  requires  too  much  blood  for  its  adop- 
tion as  a  routine  clinical  method,  although  the  quantity  required,  two 
drops,  is  not  great.  The  chief  sources  of  error  are  in  the  difficulty  of 
thoroughly  cleaning  the  tube,  and  inaccuracy  in  the  use  of  the  scales. 
Schmaltz  found  by  controlling  his  results  by  the  use  of  salt  solutions 
of  known  density  that  the  error  did  not  exceed  .003  in  the  computed 
gravities. 

Comparing  the  percentage  of  Hb  obtained  by  Fleischl's  method 
with  the  specific  gravity  obtained  by  his  own  method,  Schmaltz  con- 
structed the  following  table  : 

Specific  Gravity.  Hb.  Specific  Gravity.  Hb. 

1030     20  percent,  dr  1049       60  percent. 

1035     30        "  1051       65       " 

1038     35        "  1052       70       " 

1041     40        "  1053.5   75       " 

1042.5 45        "  1056       80       " 

1045.5 50        "  1057.5   90       " 

1048     55        "  1059 100       " 


ESTIMATION    OF    THE    ALKALESCENCE    OF    THE    BLOOD. 

The  determination  of  the  alkalescence  of  the  blood  is  attended  with 
very  great  practical  difficulties.  This  alkalescence  being  referable  to 
the  presence  of  carbonates,  bicarbonates,  and  of  albumens  which  are 
retained  in  solution  by  acid  phosphates,  it  is  always  difficult  to  judge 
of  the  changes  in  these  principles  and  the  consequent  variations  in  re- 
action produced  by  the  procedures  required  in  alkalimetry.  If  serum 
alone  is  titrated,  the  alkaline  principles  of  the  clot  are  left  out  of  ac- 
count, and  if  "  laked  "  blood  is  employed,  there  is  an  uncertain  factor 
in  the  chemical  changes  produced,  especially  in  the  delicately  balanced 
albumens  and  phosphates,  during  the  solution  of  red  cells. 

Nevertheless  it  appears  from  a  considerable  number  of  painstaking 
studies  by  Landois,  v.  Jaksch,  Kraus,  Tausczk,  Lowy,  Schultz- 
Schultzenstein,  Limbeck,  and  many  others,  that  in  blood  and  in 
serum   there   is  a  fairly  constant  group  of  alkaline  principles  which 


52 


GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 


may  be  rather  accurately  measured  and  which  have  a  distinct  and  im- 
portant relation  to  disease  (cf.  Blood  in  Fever). 

Four  of  the  many  methods  employed  may  be  recommended  as  most 
reliable. 

1.  Lowy's  Method. — In  a  50-cc.  flask  containing  45  cc.  of  2-per- 
cent solution  of  ammonium  oxalate,  5  cc.  or  less  of  fresh  blood  are 
accurately  measured,  and  dissolved. 

Of  the  solution  5  cc.  are  titrated  by  means  of  a  J^  normal  solution 
of  tartaric  acid,  using  litmus  paper  as  an  indicator.  The  latter  may 
be  prepared  by  soaking  prepared  paper  in  an  alcoholic  solution  of 
litmus  to  which  dilute  HCl  has  been  added  till  a  violet  color  appears. 
The  end  reaction  is  obtained  by  adding  a  drop  of  blood  solution  to 
the  paper  and  closely  inspecting  the  color  of  the  outer  zone  into  which 
the  fluid  diffuses.    The  result  is  not  affected  by  changes  in  temperatures. 

Engel's  Alkalimeter. — Engel  has  devised  an  apparatus  for  the  clin- 
ical estimation  of  alkalinity  according  to  Lowy's  method.  A  large 
drop  of  blood  is  drawn  into  a  special  pipette  up  to  the  mark  0.05  and 
diluted  with  distilled  water  to  the  mark  5.0.  After  shaking,  the  dis- 
solved blood  is  discharged  into  a  glass  cylinder  and  titrated  by  -^-^ 
normal  solution  of  tartaric  acid  (ac.  tartar.  1  gr.,  aq.  dest.  1  1.).     The 


Fig.  17. 


Eugel's  alkalimeter. 

acid  is  added  drop  by  drop  until  a  distinct  red  zone  appears  when  a 
drop  of  blood  is  allowed  to  diffuse  through  litmus  paper.  In  normal 
blood  about  10  drops  of  acid  bring  the  end  reaction. 

Computation. — If  .4  cc.  of  acid  are  required  to  neutralize  .05  cc.  of 
blood,  8  cc.  of  acid  will  be  required  to  neutralize  1  cc.  of  blood.  One 
cubic  centimeter  of  j\  normal  tartaric  acid  neutrahzes  .533  mg.  NaOH 
(Engel),  so  that  8  cc.  of  acid  solution  indicate  the  presence  in  1  cc.  of 


ESTIMATION  OF  OSMOTIC  TENSION  OF  THE  PLASMA.         53 

blood  of  4,264  mg.  of  NaOH,  to  wbich   terms  the  alkalinity  of  the 
blood  is  usually  reduced. 

2.  Method  of  Schultz-Schultzenstein. — By  means  of  the  pipette 
of  the  Fleischl  hemoglobinometer,  5  or  7.5  mg.  of  blood  are  measured, 
which  is  dissolved  in  12  cc,  of  distilled  water.  This  is  acidified  by 
adding  1.5  cc.  y^-g-  normal  H.,SO^.  After  careful  mixing  a  drop  or 
two  of  ethereal  solution  of  erythrosin  is  added  as  an  indicator  and  the 
solution  titrated,  with  frequent  stirring,  by  g-^^-  normal  solution  of 
KOH.  The  end  reaction  is  shown  by  the  first  appearance  of  a  red 
color  in  the  supernatant  ether.  The  test  must  be  performed  speedily, 
to  avoid  obscuring  the  end  reaction  by  a  layer  of  fibrin  precipitated  by 
the  ether. 

The  requirement  of  a  very  small  quantity  of  blood  renders  this 
method  specially  suitable  for  clinical  purposes. 

3.  V.  Limbeck's  Method, — To  about  200  cc,  of  boiled  distilled 
water  are  added  5  cc,  decinormal  HCl  solution,  and  drop  by  drop,  with 
stirring,  5  cc,  of  serum  spontaneously  expressed  from  a  clot.  The  stir- 
ring rod  should  be  covered  with  black  gutta  percha.  The  resulting 
clear  and  slightly  opalescent  fluid  is  now  titrated  with  deci-normal  so- 
lution of  NaOH.  After  adding  a  few  drops  a  precipitate  forms  which 
soon  dissolves.  The  end  reaction  is  reached  when  the  abundant  pre- 
cipitate (of  albumen)  no  longer  dissolves,  which  is  best  determined  by 
finding  a  flocculent  precipitate  persisting  on  the  black  rod. 

The  same  quantity  (5  cc.)  of  fresh  blood  may  be  titrated  by  this 
method  and  the  total  alkalinity  of  the  blood  determined.  In  adding 
blood,  however,  it  must  be  dropped  very  carefully  into  the  hot  water, 
to  avoid  coagulation. 

The  chief  technical  difficulty  with  this  method  lies  in  detecting  the 
end  reaction.  In  case  of  doubt  the  precipitate  may  be  dissolved  by 
adding  1-2  cc.  of  acid,  as  above,  and  titrating  as  before. 

There  is  also  the  objection  that  it  takes  no  account  of  the  alkalinity 
referable  to  albumens.  Limbeck  doubts,  however,  if  the  capacity  of 
albumens  to  neutralize  acids  ever  comes  into  action  in  the  body,  and 
argues  that  his  method  estimates  exactly,  without  regard  to  the  quan- 
tity of  albumen,  the  alkalinity  of  the  salts  present  in  the  blood, 

4.  Wright  has  devised  and  extensively  used  one  of  the  most 
practical  clinical  methods  of  estimating  the  alkalinity  of  the  blood  for 
the  full  explanation  of  which  the  reader  should  consult  the  original 
description. 

Determination  of  the  Coagulability  of  the  Blood. 

Vierordt  and  Wright  have  employed  methods  of  determining  the 
coagulability  of  the  blood  the  results  from  which  do  not  appear  to  be 
sufficiently  accurate  even  for  clinical  purposes.     (Limbeck.) 

Estimation  of  the  Osmotic  Tension  of  the  Plasma. 

Although  comparatively  little  attention  is  usually  paid  to  the  osmotic 
tension  of  the  plasma,  it  is  evident  from  the  frequent  occurrence  of 


54  GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 

hemoglobiaemia  in  various  forms  of  severe  anemia,  malarial  and  espe- 
cially hemoglobinuric  fever,  jaundice,  acute  poisonings,  etc.,  that  the 
condition  of  the  blood  in  this  respect  is  of  prime  importance  in  the 
clinical  and  pathological  study  of  these  diseases.  In  Hammerschlag^ s 
method  we  possess  ready  and  very  exact  means  of  investigating  this 
problem. 

In  a  series  of  test  tubes  are  poured  small  quantities,  accurately 
measured,  of  the  serum  to  be  examined,  and  to  each  is  added  an  in- 
creasing quantity  of  distilled  water.  The  surface  of  the  mixed  fluids 
in  each  tube  is  then  touched  with  a  pipette  holding  a  very  little  normal 
blood,  and  the  tubes  are  allowed  to  stand  twelve  hours.  By  that  time 
the  cells  have  settled  to  the  bottom  in  some  tubes,  while  in  others  the 
supernatant  fluid  is  tinged  with  dissolved  Hb,  and  one  notes  that  tube 
in  which  the  first  traces  of  Hb  appear.  Normal  red  blood-cells  begin 
to  lose  their  Hb  in  solutions  of  salt  containing  any  less  than  .46  per- 
cent of  NaCl.  Estimated  in  terms  of  NaCl  that  tube  of  the  series 
which  shows  the  first  faint  traces  of  dissolved  Hb,  therefore  shows  the 
same  osmotic  tension  as  a  .46-percent  solution  of  salt.  The  dilution 
being  known  the  tension  of  the  original  serum  can  be  computed  as  fol- 
lows :  Suppose  that  to  1  cc.  of  serum  .9  cc.  of  water  added,  caused  the 
solution  of  Hb.  Then  the  tension  of  the  original  serum  is  equivalent 
to  1  -h  .9  X  .46  =  .874  percent  of  NaCl. 

Bremer's  Specific  Reaction  of  Diabetic  Blood. 

Saturated  watery  solutions  of  eosin  (watery  ?)  and  of  methylene- 
blue  are  mixed  in  about  equal  proportions  so  that  a  neutral  reaction  is 
obtained,  and  the  mixture  produces  little  or  no  stain  on  litmus  paper. 
A  precipitate  forms,  soluble  in  alcohol,  insoluble  in  water,  which  is 
filtered,  washed,  dried,  and  powdered.  To  24  parts  of  this  powder 
are  added  six  of  powdered  methylene-blue  and  one  of  eosin.  Of  this 
mixed  reddish  brown  powder  .025  to  .05  grm.  are  dissolved  in  10  cc. 
of  33-percent  alcohol,  in  which  solution  the  specimen  is  stained  for 
four  minutes. 

The  specimens  are  prepared  by  smearing  tlie  blood  on  glass  slides 
or  covers,  and  fixed  by  boiling  in  equal  parts  of  alcohol  and  ether  for 
four  minutes.  This  may  be  accomplished  by  placing  the  bottle  of 
alcohol  and  ether  in  hot  water  at  60°  C. 

After  washing  the  stained  specimens  in  water,  diabetic  blood  has  a 
greenish  tint,  while  normal  blood  is  reddish  violet,  and  on  microscop- 
ical examination  the  erythrocytes  of  diabetic  blood  are  found  to  be 
greenisli,  while  those  of  normal  blood  are  red. 

Bremer  found  the  reaction  in  50  out  of  51  cases  of  diabetes.  The 
negative  result  was  obtained  in  a  well-established  case,  a  boy  of  six- 
teen, in  whom  glycosuria  began  after  an  electric  shock.  He  found 
that  the  reaction  persisted  in  the  absence  of  glycosuria  ;  that  normal 
blood  floated  on  diabetic  urine  for  15  minutes  gave  the  reaction  ;  that 
blood  treated  with  solutions  of  glucose  failed  to  give  the  reaction  ; 


DEMONSTRATION    OF  GLYCOGEN  IN  BLOOD.  55 

that  the  blood  iu  glycosuria  artificially  produced  in  animals  by  pliloro- 
glucin  gave  the  reaction,  while  in  that  produced  by  phloridzin  it  did 
not. 

The  nature  of  the  reaction  is  not  understood.  While  some  observers 
have  convinced  themselves  that  the  presence  of  glucose  is  not  sufficient 
to  bring  about  the  altered  staining  qualities  of  the  blood,  Hartwig 
concluded  that  the  glucose  first  causes  a  change  in  the  Hb  which 
shows  itself  in  the  altered  reaction  of  the  red  cells  to  anilin  dyes. 

Various  modifications  of  the  above  most  approved  method  have 
been  employed  successfully  by  Bremer  and  others.  One  of  these,  em- 
ployed by  Bremer,  is  as  follows  :  1 -percent  solutions  of  Congo  red 
or  of  methylene-blue  stain  diabetic  blood  very  slightly,  while  1 -per- 
cent solution  of  Biebrich-scarlet  stains  it  intensely.  A  directly  op- 
posite relation  holds  with  normal  blood.  Rather  thick  smears  of  blood 
should  be  used  with  this  procedure,  and  the  colors  compared  by  the 
naked  eye. 

The  value  of  Bremer's  test  has  been  confirmed  by  Le  Goff,  Eichner 
and  Folkel,  Lepine  and  Lyonnet,  James,  Jeanselme,  Badger,  and  Hart- 
wig,  but  similar  reactions  have  been  found  in  normal  blood  in  leu- 
kaemia, Hodgkin's  disease,  exophthalmic  goitre,  and  multiple  neuritis. 
A  partial  reaction  has  been  obtained  in  cachectic  conditions,  and  Bremer 
failed  to  find  it  in  a  case  of  glycosuria  of  neurotic  origin.  Yet  in 
most  conditions,  other  than  diabetes,  the  reaction  has  been  found,  when 
present,  to  be  inconstant,  and  to  occur  in  a  very  small  proportion  of 
cases  (Lepine,  Eichner,  Hartwig). 

The  technical  difficulties  in  carrying  out  the  test  are  considerable, 
while  a  slight  variation  in  technique  appears  to  vitiate  the  result,  as  is 
indicated  by  the  failures  reported  by  Patella  and  Mori,  after  both 
Bremer's  and  Williamson's  methods. 

Williamson  finds  that  diabetic  blood  decolorizes  solutions  of  meth- 
ylene-blue, while  normal  blood  does  not.  His  test  is  performed  as  fol- 
lows :  20  cmm.  (2  drops)  of  blood  are  dissolved  in  40  cmm.  of  water 
and  to  the  solution  is  added  1  cc.  of  methylene-blue  (1-6,000  solution) 
and  40  cmm.  of  Liquor  Potassce  (s.  g.  1.058).  The  vessel  is  then 
placed  in  boiling  water  for  four  minutes ;  diabetic  blood  decolorizes 
the  solution,  normal  blood  leaves  it  deep  blue.  Diabetic  urine  has  the 
same  effect. 

Williamson  found  this  reaction  in  6  diabetics  and  failed  to  find  it  in 
160  cases  of  other  diseases,  including  one  of  leukemia. 

Demonstration  of  Glycogen  in  Blood. 

Gabritschewsky's  method  may  be  employed.  The  blood  smears 
thoroughly  dried  in  the  air,  are  stained  for  several  minutes  in  :  iodum 
pur.  1  ;  KI,  3  ;  aq.,  100  ;  acacia  pulv.  in  excess. 

The  presence  of  glycogen  is  indicated  by  the  appearance  of  mahog- 
any-brown granules  of  variable  size,  in  leucocytes  and  plasma.  (See 
Plate  X.,  Fig.  2.) 


56  GENERAL  PHYSIOLOGY  AND  PATHOLOGY. 

Czerny  claimed  that  this  method  demonstrates  the  presence  in  the 
blood  not  of  glycogen  but  of  a  carbohydrate  more  nearly  related  to 
amyloid,  Huppert's  later  studies  on  the  blood  of  animals  support  the 
behef  that  the  substance  thus  demonstrated  is  really  glycogen. 

It  is  probable  that  many  colorless  globules  visible  in  leucocytes 
treated  by  ordinary  staining  methods  are  referable  to  the  former  pres- 
ence of  glycogen,  which  is  soluble  in  water  and  of  which  the  reactions 
are  largely  destroyed  by  heat. 

Demonstration  of  Fat  in  the  Blood. 

The  blood  smear  is  fixed  in  1-percent  osmic  acid  for  24  hours  and 
counterstained  with  eosin.  The  fat  particles  are  then  stained  black. 
Since  all  that  blackens  under  osmic  acid  is  not  fat,  a  control  prepara- 

FiG.  18. 


Pronounced  lipemia.    Specimen  treated  with  osmic  acid.    Lower  half  shows  extra-cellular  fat 
globules,  upper  half  having  been  cleared  by  oil  of  turpentine.    (Gumpkecht.  ) 

tion  should  be  fixed  24  hours  in  alcohol  and  ether,  then  in  1-percent 
osmic  acid  for  24  hours,  counterstained  with  eosin,  and  the  extraction 
of  the  fat  by  ether  demonstrated  by  the  absence  of  black  particles  in 
cells  and  plasma. 

BiBLIOGEAPHY. 

Badger.     Cited  by  Cabot. 

Bergmann.     Cited  by  Limbeck,  Inaug.  Dis.,  Miinchen,  1884. 

Biernacki.     Zeit.  f.  Physiol.  Chem.,  Bd.  19,  p.  179.    Zeit.  f.  kl.  Med.,  Bd.  24,  p.  460. 

Bleibtreu.     Pfliiger"  s  Archiv,  Bd.  51,  p.  151. 


BIBLIOGRAPHY.  57 

Blix,  Hedin.     Scand.  Arch.  f.  Physiol.,  1890,  p.  134. 

Brandenburg.     Munch,  med.  Wocli.,  1900,  p.  183. 

Bremer.  N.  Y.  Med.  Jour.,  Vol.  63,  p.  301.  Ibid.,  Vol.  66,  p.  808.  Cent.  f.  inn. 
Med.,  1897,  p.  521. 

Buntzen.     Virchow-Hirsch,  Jahresb.,  1879. 

Cheron.     Compt.  Eend.  Acad.  Sci.,  1895,  Vol.  121,  p.  314. 

Cohnheim.     Vorles.  u.  Allg.  Pathol.,  Berlin,  1882,  Bd.  I.,  p.  397. 

Cohnstein,  Zimtz.     Pfliiger  s  Archiv,  1888,  Bd.  42. 

Czerny.     Archiv  f.  exp.  Path.  u.  Pharm.,  Bd.  34,  p.  268.     Ibid.,  Bd.  31,  p.  190. 

Daland.     Fort.  d.  med.,  1891,  No.  21. 

Elzholz.     Wien.  klin.  Woch.,  1894,  No.  32. 

Enqel.     Berl.  klin.  Woch.,  1898,  p.   308. 

Eichner,  Folkel.     Wien.  klin.  Woch.,  1897,  p.  1103. 

Eyckman.     Arch.  f.  ges.  Physiol.,  1895,  Bd.  40,  p.  340. 

Oabritschewsky.     Arch.  f.  exper.  Path.,  Bd.  28,  p.  272. 

Gartner.     Allg.  Wiener  med.  Zeit.,  1892,  p.  513. 

Gartner,  Romer.     Wien.  klin.  Woch.,  1892,  No.  2. 

Grawitz.  Zeit.  f.  klin.  Med.,  Bd.  21,  Bd.  22.  Methodik  d.  kl.  Blutuntersuch,  Ber- 
lin, 1899. 

Hamburger.  Die  phvsiol.  Kochsalzlos.  u.  d.  Volumbestimmung  d.  korperl.  Ele- 
mente  im  Blute.  Cent.'f.  Physiol.,  1893,  1894,  p.  656.  Virchow's  Archiv,  Bd.  141, 
p.  230. 

Hammerschlag.     Wien.  klin.  Woch.,  1890,  p.  1018. 

Hartwig.     Deut.  Arch.  klin.  Med.,  Bd.  62,  p.  287. 

Hedin.     Arch.  f.  ges.  Physiol.,  Bd.  40,  p.  360. 

Heidenhain.  Versuch.  zur  Lehre  von  der  Lymphbildung,  Pfliiger's  Archiv,  1891, 
Bd.  49,  p.  209. 

Heissler.     Arbeit,  aus  d.  path.  Instit.  zu  Miinchen,  1886,  p.  322. 

Huppert.     Zeit.  f.  Physiol.  Chem.,  Bd.  18,  p.  144. 

Jacobi,  31.  P.     N.  Y.  Med.  Eecord,  1898,  I.,  p.  933. 

V.  Jaksch.     Zeit.  f.  klin.  Med.,  Bd.  13. 

Klein.     Volkmann's  Vortriige,  No.  29. 

Knopf elmacher.     Wien.  klin.  Woch.,  1893,  pp.  810,  886. 

Kraus.     Arch.  f.  exper.  Path.,  Bd.  26,  p.  186. 

Landois.     Text-book  of  Physiol.,  1893. 

Lepine,  Lyonnet.     Lyon  Med.,  T.  82,  p.  187. 

Le  Goff.     React,  chrom.  du  sang  diabet,  Paris,  1897. 

Leichtenstern.     Unters.  u.  d.  Hemoglobingehalt  d.  Blutes,  Leipzig,  1878,  p.  57. 

V.  Lesser.  Sitzungsber.  d.  k.  Siichs.  Gesell.  d.  Wissenschaften,  1873,  p.  573  ;  1874, 
p.  153.     Du  Bois-Reymond's  Archiv,  1878,  p.  41. 

von  Limbeck.     Grundriss  einer  klin.  Path.  d.  Blutes,  Jena,  1897,  p.  68. 

Lloyd  Jones.     Journal  of  Physiol.,  1887,  viii. 

Lowit.     Studien  z.  Phys.  u.  Path.  d.  Blutes,  etc.,  Jena,  1892. 

Lowy.  Pfliiger's  Archiv,  Bd.  58,  p.  462.  Cent.  f.  med.  Wissen.,  1894,  p.  785. 
Fort.  d.  Med. ,"'1898,  p.  171. 

Ludwig.     Cited  by  Lukjanow. 

Lukjanow.     Grundziige  ein.  allg.  Path,  des  Gefiiss-systems,  Leipzig,  1894. 

Lyon,  Thoma.     Virchow's  Archiv,  Bd.  84,  p.  131. 

Mitchell.     Amer.  Jour.  Med.  Sci.,  Vol.  107,  p.  502. 

MuUer,  Rieder.     Deut.  Arch.  klin.  Med.,  Bd.  48,  p.  96. 

Oertel.     Klinische  Zeit-  u.  Streitfragen,  Wien,  1889. 

Patella,  Mori.     Gaz.  deg.  Osped.,  1896,  IL,  p.  1441. 

Pepper,  Stengel.     Cong.  f.  inn.  Med.,  1896,  p.  631. 

Pfeiffer.     Ibid.,  1895,  No.  4. 

Reinert.     Zahlung  der  Blutkorp,  Leipsic,  1891. 

V.  Recklinghausen.  Handb.  der  allg.  Path.  d.  Kreislaufs  u.  der  Ernahrung,  Stutt- 
gart, 1883,  p.  179. 

Schmaltz.     Arch.  f.  klin.  Med.,  Bd.  47,  p.  145. 

Schidtz-Schultzenstein.    Cent.  f.  med.  Wissen.,  1894,  p.  801. 

Siegel.     Wien.  klin.  Woch.,  1891,  No.  33. 

Stintzing,  Gumprecht.     Deut.  Arch.  f.  klin.  Med.,  Bd.  53,  p.  265. 

Tauczk.     Ungar.  Arch.  f.  Med.,  1895,  p.  359. 

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Thibault.     Bull.  Acad.  Med.  Bruxelles,  1894,  p.  112. 

Valentin.     Reporter,  f.  Anat.  u.  Physiol.,  1838,  Bd.  3,  p,  281. 


58  GENERAL  PHYSIOLOGY  AND  PATHOLOGY 

Vierordt.     Arch.  f.  Heilk.,  1878,  Bd.  19,  p.  193.     Wagner's  Handb.  d.  Physiol. 
1842,  Bd.  1,  p.  84. 

Wenddstadt,  Bleibtreu.     Zeit.  f.  klin.  Med.,  Bd.  25,  p.  204. 

Wick.     Wien.  med.  Zeit.,  1887. 

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Wright.     Lancet,  1897,  II.,  pp.  719,  814,  833.     ^ Lancet,  1892,  I.,  pp.  457,  515. 

Zappert.    Zeit.  f.  klin.  Med.,  Bd.  23,  p.  227. 


CHAPTER    II. 
CHEMISTRY   OF   THE   BLOOD. 

THE    CHEMICAL    COMPOSITION    OF    RED    BLOOD    CELLS. 

In  the  analyses  of  Schmidt,  Hoppe-Seyler,  and  Judell,  the  red  cells 
were  separated  from  the  serum  by  the  addition  of  salts  (Na,,SO^,  NaCl), 
a  procedure  which  considerably  alters  the  chemical  composition  of  cells 
and  plasma.  The  accuracy  of  their  results,  which  are  the  best  avail- 
able, is  therefore  only  approximate. 

The  specific  gravity  of  red  cells  is  usually  about  1.088.  They  con- 
tain about  90  percent  of  oxyhemoglobin  and  a  small  proportion  of  a 
globulin-like  albumen  (nucleo-proteid)  coagulating  at  75°  C.  There 
are  also  traces  of  lecithin  and  cholesterin.  The  principal  salts  are 
phosphates  of  Na,  K,  Ca,  and  Mg,  and  chloride  of  K,  whereas  in  the 
serum  the  chief  salt  is  NaCl. 

In  cholera,  dysentery,  and  dropsy,  Schmidt  found  the  red  cells  to 
be  of  increased  specific  gravity  in  proportion  to  the  duration  of  the 
exudative  process,  while  their  chemical  analysis  showed  that  they  par- 
ticipate in  the  changes  which  first  affect  the  serum,  losing  first  water, 
then  salts,  and  finally  albumen.  More  recently,  v.  Jaksch,^  after  es- 
tablishing the  normal  content  in  N  of  the  red  cells,  followed  the  varia- 
tions in  this  principle  in  various  diseases.  He  found  very  marked 
and  irregular  variations  both  in  health  and  disease,  which  indicate  that 
the  method  used  (determination  of  total  N)  was  unreliable. 

Biernacki,  estimating  the  dry  residue  of  red  cells  settled  after  the 
addition  of  sodium  oxalate,  found  a  normal  residue  of  29.28—30  per- 
cent ;  in  carcinoma  of  esophagus  27.9  percent ;  in  tabes  with  anemia, 
25.51  percent ;  in  chlorosis  (Hb  25  percent)  22.24  percent  ;  in  chronic 
nephritis  (Hb  20  percent)  22.88  percent.  Among  the  important  ob- 
servations of  Biernacki's  are,  the  increased  content  in  water  of  the  red 
cells  in  hydremia ;  the  general  parallelism  between  P.,0.,  Fe,  and  K, 
and  between  water  and  NaCl,  in  the  red  cells. 

Hemoglobin  (Hb)  and  its  Derivatives. 

Hemoglobin  belongs  to  the  group  of  proteids,  containing  about  96 
percent  of  albumen,  and  4  percent  of  an  iron-holding  pigment,  hemo- 
ckromogen.  Hb  exists  in  the  red  cells  in  combination  probably 
with  the  nucleo-proteid  of  the  stroma.  The  nature  of  this  union  is  not 
certainly  understood,  but  it  renders  Hb  comparatively  insoluble, 
greatly  concentrated,  and  capable  of  actively  forming  unstable  com- 
pounds with  oxygen.     (Hoppe-Seyler,  Gamgee.) 


60  CHEMISTRY  OF  THE  BLOOD. 

Its  chemical  composition  is  very  complex  and  apparently  variable, 
but  its  spectroscopic  relations  are  constant.  In  the  circulation  it  exists 
principally  as  reduced  Hb  in  the  veins,  and  in  molecular  union  with 
oxygen  as  oxyhemoglobin,  in  the  arteries.  One  gram  of  saturated  oxy- 
hemoglobin yields  about  I.IG  cc.  of  oxygen,  but  in  the  circulation  the 
degree  of  saturation  with  oxygen  varies  and  in  health  is  never  com- 
plete. Meyer  and  Biarnes  found  in  the  arterial  blood  of  a  dog  76  per- 
cent of  saturation  with  oxygen  ;  after  a  large  hemorrhage  it  rose  to 
85  percent  of  saturation,  while  after  inducing  CO  poisoning  it  rose 
to  90  percent.  Limbeck  found  97  percent  of  saturation  with  oxy- 
gen in  the  blood  of  a  dog  poisoned  with  potassium  chlorate.  It  thus 
appears  that  with  a  relative  loss  of  functionating  Hb,  the  demands  of 
the  system  may  cause  a  more  complete  saturation  of  the  blood  with 
oxygen  than  exists  in  health. 

Oxyhemoglobin  is  bright  red  in  color,  and  forms  with  difficulty 
yellowish-red  rhombic  crystals.  These  crystals  are  very  soluble  in 
water  and  in  very  dilute  solutions  of  alkaline  carbonates,  but  when 
treated  with  strong  alcohol  they  are  modified  and  become  insoluble 
(parheraoglobin  of  Nencki).  They  are  insoluble  in  ether,  chloroform, 
benzol,  or  carbon  disulphide.  Oxyhemoglobin  is  absolutely  non-dif- 
fusible.    (Gamgee.) 

Hemoglobin  (Reduced  Hb)  is  dichroitic.  In  thick  layers,  or  in 
thin  layers  of  concentrated  solutions,  it  presents  a  dark  cherry-red 
color,  while  very  dilute  solutions  exhibit  a  green  tint.  (Gamgee.)  This 
dichroism  is  characteristic  of  the  blood  of  simple  asphyxia.  Reduced 
Hb  is  more  soluble  but  less  easily  crystallizable  than  oxyhemoglobin. 

Methemoglobin  is  brownish  red  in  color,  readily  soluble  in  water, 
and  crystallizes  in  brownish  red  needles,  prisms,  and  hexagonal  plates. 
It  contains  the  same  proportion  of  oxygen  as  oxyhemoglobin,  but  in 
much  firmer  and  probably  in  chemical  union.  Methemoglobin  is 
found  in  the  blood  chiefly  in  cases  of  poisoning  by  a  variety  of  sub- 
stances, the  so-called  -'blood  poisons."  Tschirkoflf  claims  to  have 
found  it  in  Addison's  disease,  and  Ruyter  has  recognized  a  very  similar 
but  not  identical  coloring-matter  in  a  case  of  malignant  oedema. 

Hemoglobinemia,  a  solution  of  Hb  in  the  plasma,  a  normal  con- 
dition in  the  blood  of  some  vertebrates,  is  in  man  always  pathological, 
and  results  from  lessened  resistance  on  the  part  of  the  red  cells,  and 
from  abnormal  states  of  the  plasma.  The  former  condition  is  probably 
concerned  in  cases  of  paroxysmal  hemoglobinemia  and  in  the  destruc- 
tion of  blood  which  follows  general  burns  (Lichtheim,  Murri,  Chvostek, 
Silberman),  while  the  latter  condition  exists  in  the  hemoglobinemia  of 
acute  poisonings  and  in  cases  referable  to  increased  globulicidal  power 
of  the  serum. 

Carbonic  oxide  Hb  is  a  firm  compound  of  Hb  and  CO,  and  im- 
parts a  bluish  red  or  rose-red  color  to  the  blood.  Its  crystals  are 
similar  to  those  of  oxyhemoglobin  but  more  bluish  and  less  soluble. 
In  cases  of  poisoning  by  the  inhalation  of  fire-damp  or  illuminating 
gas,  CO-Hb  is  formed  in  considerable  proportion  and  the  respiratory 


THE  CHEMICAL   COMPOSITION  OF  LEUCOCYTES.  61 

capacity  of  the  blood  is  largely  destroyed.  CO-Hb  persists  in  the 
blood  for  several  days,  in  cases  that  recover,  and  for  a  mnch  longer 
period  in  fatal  cases. 

Hem.vtix,  one  of  the  advanced  decomposition  products  of  Hb,  is 
a  dark  brown  or  blackish,  non-crystalline  solid,  decomposed  at  180°  C. 
It  is  insoluble  in  water,  dilute  acids,  alcohol,  ether  and  chloroform, 
but  dissolves  in  acidified  alcohol  and  ether,  and  readily  in  dilute 
alkalies.  It  is  found  in  old  bloody  transudates,  in  the  feces  where 
digestive  fluids  have  acted  npon  blood,  and  in  the  urine  in  cases  of 
arsenical  poisoning.  Crystals  of  hnemin,  or  the  hydrochlorate  of  hem- 
atin,  are  formed  in  Teichmann's  test. 

Hematoidix  is  a  crystalline  derivative  of  Hb,  found  in  old  blood 
extravasations.  It  crystallizes  in  orange-colored  rhombic  plates,  is 
soluble  in  chloroform,  ether,  carbon  disulphide,  and  ammonium  sul- 
phide, contains  no  iron,  and  gives  no  absorption  bands  although 
absorbing  most  of  the  violet  end  of  the  spectrum.  It  is  generally 
regarded  as  identical  with  bilirubin. 

Hemosiderix  is  an  amorphous  iron-holding  product  of  the  decom- 
position of  Hb,  and  is  abundantly  found  in  the  viscera  in  disease  accom- 
panied by  much  destruction  of  blood.  It  is  probable  that  when  red 
cells  are  disintegrated  hemosiderin  is  formed  by  the  action  of  living 
cells  upon  Hb,  while  hematoidin  originates  apart  from  any  cellular 
activities.  (Perls,  Thoma,  Ziegler.)  Hemosiderin  is  blackened  by  am- 
monium sulphide  and  turned  blue  by  acidified  potassium  ferrocyanide. 

Melaxix  is  a  yellowish  brown  or  black  pigment  produced  by  the 
action  of  the  malarial  parasite  upon  Hb.  It  is  insoluble  in  water, 
alcohol,  ether,  chloroform,  carbon  disulphide,  and  acids  in  moderate 
strength,  but  is  destroyed  by  heat,  and  is  soluble  in  strong  alkalies 
and  in  ammonium  sulphide.  It  fails  to  yield  the  micro-chemical  reac- 
tions of  iron,  and  probably  contains  no  iron. 

The  term  "  melanin  "  is  also  loosely  applied  to  a  variety  of  black 
pigments  occurring  in  the  body,  some  of  which  contain  iron  but  whose 
origin  is  uncertain. 

From  "  antialbumid,"  formed  by  heating  egg-albumin  witli  3-pei'cent 
HjSO^  for  10  liours  at  100°  C,  and  fi*om  hemipeptone,  Chittenden  and  Albro 
produced  black  melanin,  by  digesting  these  substances  with  10 -percent 
H2SO4  and  boiling  for  79  hours.  The  change  they  believe  to  consist  in  a 
process  of  hydrolytic  cleavage.  Sulphur  and  fatty  acids  were  thrown  off  in 
the  process  and  the  melanin  was  found  to  contain  C,  H,  N,  and  S. 

THE  CHEMICAL  COMPOSITION  OF  LEUCOCYTES. 

Attempts  to  determine  the  chemical  composition  of  leucocytes  have 
been  made  by  analyses  of  leukemic  blood,  of  pus,  and  of  fresh  lymph- 
oid tissue.  In  all  of  these  it  cannot  be  doubted  that  abnormal 
products  were  constantly  present,  so  that  the  chemical  composition  of 
normal  leucocytes  cannot  be  learned  by  such  methods.  Probably 
Lilienfeld's  analyses^  of  lymphoid  tissue  furnish  the  most  reliable 
data. 


62  CHEMISTRY  OF  THE  BLOOD. 

In  cadaveric  leukemic  blood  various  fatty  acids  have  been  isolated, 
and  lecithin,  a  normal  constituent  of  blood,  has  been  found  in  excess. 
Glycogen  has  been  repeatedly  isolated  in  this  and  other  conditions. 

In  fresh  pus,  Miescher  found  five  diiferent  forms  of  albumen,  an 
abundance  of  lecithin,  and  cholesterin,  phosphates  of  Na,  K,  Ca,  Mg, 
Fe,  and  chloride  of  Na. 

In  analyses  of  the  thymus  gland  in  calves  Kossel  and  Lilienfeld 
isolated  various  albumens,  principally  nucleins,  lecithin,  and  chole- 
sterin, besides  about  3  percent  of  inorganic  principles.  In  older  cells 
they  believe  that  secondary  products  develop  in  the  form  of  glycogen, 
protagon,  and  fats. 

The  nuclein  of  Kossel  is  a  combination  of  the  organic  nucleinic  acid  which 
contains  phosphorus,  with  albumen,  and  in  the  leucocytes  is  found  in  com- 
bination with  another  albuminous  body,  histon,  with  which  it  forms  nucleo- 
histon.  Under  certain  conditions  Kossel  and  Lilienfeld  believe  that  nucle- 
inic acid  becomes  free  in  the  cells,  and  exerts  bactericidal  action  before  and 
during  phagocytosis. 

The  nucleins  are  bodies  obtained  from  animal  (or  vegetable)  cells 
after  digestion  with  pepsin  to  which  they  are  resistant.  They  are 
rather  insoluble  in  water,  alcohol,  and  ether,  give  the  biuret  and  Mil- 
Ion's  reactions,  and  acting  as  strong  acids  and  uniting  with  bases,  they 
may  be  identified  from  the  basic  albumens  by  their  tinctorial  qualities. 
Boiled  with  dilute  acids  they  yield  "  nuclein-bases  "  or  xanthin-bodies  ; 
or  treated  with  alkali  they  yield  albumen  and  nucleinic  acid.  They 
are  rich  in  phosphorus  and  iron.  Nucleinic  acid  is  of  variable  com- 
position, but  that  from  the  calf's  thymus  is  a  combination  of  a  xanthin 
body  with  a  complex  phosphoric  acid.     (Hammarsten.) 

THE  CHEMICAL  COMPOSITION  OF  BLOOD  PLATES. 

Since  the  true  nature  of  blood  plates  has  been  at  least  partly  shown, 
the  chief  inquiry  concerning  them  has  related  to  their  chemical  com- 
position. Lowit  has  strongly  maintained  that  they  are  composed  of 
globulin,  a  claim  which  is  probably  true  of  some  of  the  bodies  which 
appear  in  coagulating  shed  blood  and  which  must  be  classed  with  the 
blood  plates  of  different  origins. 

Lilienfeld  ^  regards  the  substance  of  blood  plates  as  belonging  to  the 
nucleo-albumens,  and  identifies  them  with  the  remnants  of  the  nuclei 
of  leucocytes,  basing  this  opinion  on  their  content  in  phosphorus, 
their  resistance  to  digestion  by  pepsin,  and  their  micro-chemical  reac- 
tions. These  observations  may  be  regarded  as  definitely  settling  the 
question  of  their  chemical  composition,  but  do  not  prove  their  exclu- 
sive origin  from  leucocytes. 

THE  SERUM. 

The  Albumens  of  the  Serum. — Blood  serum  contains  two  albu- 
minous bodies,  serum  albumen   and  serum   globulin,  which  together 


THE  SERUM.  63 

form  7,62  percent  (Hammarsten),  or  8.26  percent  (Schmidt)  of  the 
weight  of  normal  serum. 

The  quantitative  changes  in  these  principles  in  disease  are  not  usu- 
ally very  marked,  owing  to  their  relatively  slight  diffusibility. 

From  the  studies  of  Becquerel  and  Rodier,  Schmidt,  v.  Jaksch,  Lim- 
beck and  Pick,  it  has  been  shown  that  the  albumens  of  the  serum  are 
considerably  diminished  in  severe  anemias,  and  in  nephritis  or  endo- 
carditis with  dropsy,  but  that  in  most  severe  infectious  diseases  they 
are  but  slightly  reduced  and  bear  a  fairly  constant  relation  to  the  other 
solids  of  the  serum.  If  temporarily  reduced  by  some  exudative  lesion, 
as  in  diarrhea,  dysentery,  etc.,  they  are  soon  replaced  if  the  disease 
continues. 

Becquerel  and  Rodier,  however,  found  the  albumens  much  reduced 
in  puerperal  septicemia,  and  Schmidt  found  a  marked  increase  in  the 
concentrated  blood  of  cholera,  v.  Jaksch,"  determining  the  total  N  of 
the  serum,  found  slight  variations  in  many  acute  and  chronic  diseases, 
but  a  well-marked  loss  in  leukemia,  pernicious  and  secondary  anemia, 
and  chlorosis.  Limbeck,  using  the  same  method,  found  less  marked 
changes  in  cases  of  anemia. 

The  ratio  of  serum  albumen  to  serum  globulin,  on  the  other  hand, 
varies  much  more  than  does  the  total  quantity  of  albumen  in  the  serum. 
The  normal  limits  are  placed  by  Limbeck  and  Pick,  for  globulin 
16.9-38.3  percent,  for  albumen  61.7-83.1  percent  of  the  total  albu- 
men of  the  serum.  When  such  Avide  limits  may  be  found  in  nor- 
mal subjects  it  is  difficult  to  attach  much  importance  to  very  consider- 
able changes  demonstrated  in  disease,  as  reported  by  Estelle,  Hoffmann, 
Halliburton,  and  Mya  and  Viglezio.  In  a  considerable  series  of  ob- 
servations in  various  diseases  Limbeck  and  Pick  succeeded  in  showing 
only  that  serum  globulin,  the  less  diffusible  principle,  is  less  subject 
to  change  than  is  serum  albumen,  but  they  were  unable  to  establish 
any  other  general  rules. 

The  inorganic  salts  of  the  serum  include  phosphates,  chlorides, 
carbonates,  and  sulphates,  but  in  what  proportion  or  form  the  alkalies 
and  earths  are  combined  with  these  acids  is  not  definitely  known. 
Sodium  and  potassium  are  combined  especially  as  neutral  chlorides, 
partly  as  phosphates  and  carbonates.  Pathological  variations  in  the 
phosphates  of  the  serum  are  of  slight  degree  and  importance,  so  far  as 
is  known,  probably  on  account  of  their  occurrence  in  scant  quantity 
and  their  relative  lack  of  diffusibility.  A  retention  of  phosphates  in 
the  blood  of  pathological  grade  has  not  been  demonstrated.  The 
variations  in  the  chlorides  of  the  serum  investigated  by  Schmidt, 
Biernacki,  and  Limbeck  have  not  been  found  extreme,  nor  of  notable 
pathological  import,  although  this  principle  is  chiefly  responsible  for 
the  isotonic  relations  of  cells  and  serum.  A  high  percentage  of  chlo- 
rides is  usual  in  anemias. 

The  specific  gravity  of  the  serum  in  disease  varies  slightly  from 
the  normal  limits,  1.025-1.030.  (Hamraerschlag,  Limbeck.)  While 
Becquerel  and  Rodier  and  Hammerschlag  found  the  specific  gravity 


64  CHEMISTRY  OF  THE  BLOOD. 

of  the  serum  normal  in  chlorosis  but  reduced  in  secondary  anemia, 
Limbeck  found  it  low  in  both  (1.021-3).  In  infectious  diseases  Bec- 
querel  and  Rodier  found  the  serum  of  normal  gravity. 

The  color  of  human  serum  is  yellowish  with  a  slight  greenish  fluor- 
escence, but  after  a  hearty  meal  the  increased  quantity  of  fat  ruay  yield 
a  cloudy  or  whitish  color.  The  coloring  matter  of  normal  human 
serum  belongs  to  the  group  of  luteins  or  lipochromes  (Hammarsten). 
It  is  extracted  by  alcohol  and  by  ether,  yields  a  blue  color  with  iodine 
and  sulphuric  acid,  and  on  spectroscopic  analysis  causes  an  absorption 
of  the  violet  and  part  of  the  blue,  which  is  unaffected  by  reducing  or 
oxidizing  agents.  Icteric  serum  causes  more  complete  absorption,  be- 
ginning sharply  in  the  blue.     (Limbeck.) 

When,  from  lessened  resistance  of  the  red  cells  or  abnormal  con- 
ditions of  the  plasma,  red  cells  are  dissolved,  the  serum  contains  Hb 
in  solution  (hemoglobinemia),  as  occurs  principally  in  malaria,  par- 
oxysmal hemoglobinuria,  septicemia,  and  with  the  blood  poisons.  In 
jaundice,  the  serum  has  a  characteristic  orange-yellow  color  and  bili- 
rubin is  readily  detected. 

The  Globulicidal  Property  of  Serum. — When  the  serum  of  dis- 
eased subjects  is  added  to  normal  blood  the  red  cells  are  often  rapidly 
dissolved  and  the  normal  color  of  Hb  is  replaced  by  a  greenish  tint. 
On  spectroscopic  analysis,  such  a  specimen  shows  the  presence  not  of 
Hb  but  of  hematoidin. 

Maragliano,  who  first  investigated  this  property,  found  marked  globulicidal 
action  in  the  serum  of  all  grades  of  primary  anemia,  leukemia,  purpura,  pneu- 
monia, malaria,  erysipelas,  typhoid  fever,  cirrhosis,  and  nephritis.  Limbeck 
has  noted  a  greenish  color  by  the  naked  eye,  and  demonstrated  hematoidin,  in 
the  serum  of  pneumonia,  typhoid  fever,  and  purpura  hemorrhagica.  Buchner 
demonstrated  a  relation  of  the  globulicidal  activity  of  serum  and  its  con- 
tent in  salts,  finding  more  marked  activity  in  serum  poor  in  salts  and  finding 
that  the  addition  of  salts  diminishes  the  effects.  Buchner  was  also  the  first 
to  call  attention  to  the  close  relation  between  the  globulicidal  and  bacteri- 
cidal properties  of  serum.  Castellino  noted  the  toxic  effects  of  the  serum 
of  one  animal  upon  the  blood  of  another,  and  found  that  they  depended 
upon  globulicidal  and  coagulative  properties.  According  to  Mairet  and 
Bosc,  15  cc.  of  normal  human  serum  suffices  to  kill  a  rabbit  weighing  two 
pounds.  Heating  to  52-58°  C.  or  a  slight  addition  of  salt,  largely  inhibit 
the  coagulative  effect,  but  only  partly  destroy  the  toxicity  of  serum,  from 
which  facts,  principally,  Mairet  and  Bosc,  and  Hayem,  conclude  that  the 
toxicity  of  serum  depends  on  the  presence  of  an  albuminoid  body.  Castel- 
ino  finds  that  the  globulicidal,  coagulative,  and  general  toxic  properties 
vary  uniformly  in  specimens  of  serum  and  all  are  proportionate  to  the  con- 
ent  of  nuclein. 

THE   WHOLE   BLOOD. 

Albumens. — The  albuminous  principles  of  normal  circulating  blood 
include  hemoglobin,  serum  albumin,  serum  globulin,  and  fibrinogen. 
In  shed  blood  a  nucleo-proteid  exists  which  is  probably  derived  from 
the  nuclei  of  leucocytes,  probably  also  from  red  cells,  which  combines 
with  calcium  salts   to  form  the  fibrin-ferment,   and  which  is   called 


THE   WHOLE  BLOOD.  65 

'^  prothrombin."  Traces  of  albumose  have  been  found  in  the-  blood 
in  various  diseases,  and  other  nitrogenous  principles,  occasionally  pres- 
ent and  commonly  reckoned  with  the  albumens,  are  urea,  uric  acid, 
and  xanthin  bodies.  Varying  considerably  with  the  method  of  deter- 
mination, the  proportion  in  which  these  elements  exist  in  the  blood 
has  been  placed  for  the  entire  group  by  v.  Jaksch^  at  22.62  percent ; 
by  Limbeck  at  about  25  percent;  by  Schmidt  at  10.82-16.63  percent. 

A  relative  increase  of  total  albumen  is  seen,  according  to  v.  Jaksch, 
in  diseases  accompanied  by  marked  loss  of  fluids,  as  in  cholera  and 
severe  diarrhea,  but  an  absolute  increase  has  not  been  demonstrated. 
In  infectious  diseases  the  albumens  are  moderately  reduced,  even  when 
the  number  of  red  cells  remains  normal  (typhoid  fever).  In  nephritis 
there  is  usually  but  not  always  a  reduction.  In  endocarditis  there  is 
little  change.  In  chlorosis,  pernicious  anemia,  and  leukemia,  the  total 
albumens  of  the  blood  are  constantly  diminished,  but  in  secondary 
anemia  the  diminution  usually  noted  sometimes  fails,  v.  Jaksch  found 
his  lowest  proportion,  8.46  percent,  in  a  case  of  gastric  cancer. 

Peptone  has  been  demonstrated  in  the  blood  of  leukemia,  by  Ludwig, 
V.  Jaksch,^  and  Freund  and  Obermayer,  and  deutero- albumose  by  Mat- 
thes.  These  observations  were  made  on  blood  from  the  cadaver. 
Devoto  and  Wagner,  who  examined  blood  obtained  during  life,  both 
failed  to  find  peptone.  The  suspicion  that  the  peptone  previously 
demonstrated  was  of  postmortem  formation  was  followed  up  by  v. 
Limbeck  in  a  case  of  myelogenous  leukemia.  In  the  fresh  blood  no 
peptone  was  found,  but  in  a  specimen  that  had  stood  at  room  tempera- 
ture for  forty-eight  hours,  albumose  was  demonstrated,  but  its  exact 
character  was  not  determined.  The  patient  died  three  weeks  later  and 
deutero-albuniose  was  demonstrated  in  the  blood  of  the  cadaver,  v. 
Jaksch  states  that  peptone  (albumose  ?)  is  found  in  leukemic  blood 
only  when  eosinophile  cells  are  abundant.  Freund's  observation  that 
peptone  is  found  in  the  blood  in  cases  of  sarcoma  but  not  in  cases  of 
carcinoma,  has  not  yet  been  confirmed. 

The  addition  of  small  quantities  of  peptone  to  plasma  in  vitro  re- 
duces its  content  of  CO^  and  its  coagulability,  and  it  seems  probable 
that  if  peptone  (or  albumose)  exists  in  the  circulating  blood  a  similar 
influence  is  exerted,  intra  vitam,  by  its  presence. 

Quantitative  Estimation  of  Total  Albumen  of  the  Blood  may  be  ac- 
complished by  one  of  two  methods. 

1.  By  precipitating  the  albumens  by  excess  of  alcohol,  and  weighing 
the  dried  precipitate. 

2.  By  estimation  of  total  N  by  Kjeldahl's  method  and  multiplying 
the  result  by  6.25  (v.  Jaksch). 

By  the  first  method  an  uncertain  quantity  of  inorganic  matter  is  car- 
ried down  which  cannot  be  thoroughly  removed  by  washing,  and  which 
therefore  disturbs  the  result. 

In  the  second  method,  N  is  derived  from  other  principles  besides 
albumens,  and,  as  Limbeck  and  Pick  have  shown,  there  may  be  a  dif- 
ference of  10-20  percent  in  the  results  of  the  two  methods. 

5 


66  CHEMISTRY  OF  THE  BLOOD. 

Most  of  the  nitrogenous  principles  other  than  albumens  are  soluble 
in  alcohol  and  some  of  the  sources  of  error  in  this  method  are  there- 
fore removed  by  estimating  the  total  N  of  the  alcoholic  precipitate. 
V.  Jaksch  has  determined  that  by  multiplying  the  percentage  of  N  by 
6.25  the  average  percentage  of  weight  of  albumen  is  obtained.  Lim- 
beck and  Pick,  after  investigating  the  ratio  between  N  and  the  weight 
of  albumen  from  which  it  was  derived,  concluded  that  v.  Jaksch's  fig- 
ure is  sufficiently  reliable  in  the  great  majority  of  cases,  but  that  con- 
siderable inaccuracies  may  result  in  the  cases  of  venous  stasis,  nephri- 
tis, and  especially  uremia,  in  which  nitrogenous  principles  in  the 
blood  other  than  albumens  are  increased. 

The  determination  of  total  N  by  Kjeldahl's  method  is  generally  em- 
ployed in  estimating  the  albumens  of  the  blood.  The  method  may  be 
found  fully  described  in  Halliburton,  "  Chem.  Phys.  and  Path.,"  or 
Sutton,  "  Volumetric  Analysis." 

Inorganic  Principles  of  the  Blood.  The  Blood-Ash. — After  in- 
cineration of  two  specimens  of  normal  blood  Schmidt  found  .84  per- 
cent and  .91  percent  of  ash.  This  quantity  was  increased  to  1  per- 
cent in  a  case  of  cholera,  but  the  relation  of  ash  to  dry  residue 
remained  normal,  3.1-3.5  percent.  In  the  watery  blood  of  nephritis, 
however,  the  ash  was  relatively  much  increased  (6.5  percent). 

Chemical  analyses  of  the  blood-ash  in  health  and  disease  have  shown 
that  pathological  importance  attaches  principally  to  variations  in  the 
chlorides,  phosphates,  and  the  iron  of  the  blood. 

With  regard  to  the  chlorides  (principally  NaCl)  the  law  has  been 
established,  that  the  large?'  the  proportion  of  plasma  the  greater  is  the 
percentage  of  chlorides  in  the  blood.  In  pneumonia  the  chlorides  are 
low,  probably  owing  to  diminished  ingestion,  and  the  effects  of  an  ex- 
udative process  which  drains  the  blood  of  a  considerable  quantity  of 
salts.  In  typhoid  fever  and  erysipelas  a  reduction  usually  exists 
which  is  neither  so  marked  nor  so  constant.  In  nearly  all  forms  of 
anemia  the  proportion  of  chlorides  is  high,  following  the  rule  above 
stated.  Yet  Limbeck  found  normal  proportions  in  two  cases  of 
chlorosis,  which  he  refers  to  diminished  salts  in  the  red  cells,  and 
Biernacki  refers  to  cases  of  severe  anemia  with  normal  chlorides, 
which  he  also  explains  from  the  loss  of  red  cells.  Becquerel  and 
Rodier  found  considerable  variations,  but  a  normal  average  in  chlo- 
rides in  six  cases  of  chlorosis. 

From  the  known  influence  upon  the  urinary  chlorides  of  diminished 
ingestion  of  food,  vomiting,  diarrhea,  and  exudation,  it  appears  prob- 
able that  these  factors  may  to  some  extent  aifect  the  chlorides  of  the 
blood,  for  in  many  of  the  available  analyses  of  the  blood-ash  in  gen- 
eral diseases,  there  are  numerous  contradictory  results  (tuberculosis, 
syphilis,  cancer). 

The  phosphates  exist  as  neutral  or  alkaline  salts  of  Na,  Ca,  Mg,  in 
the  plasma  and  in  various  combinations  (lecithin,  nuclein),  in  the  red 
and  white  cells.  Few  facts  of  importance  have  been  established  in 
regard  to  the  variations  in  these  principles  of  the  blood. 


I 


INORGANIC  PRINCIPLES  OF  THE  BLOOD.  G7 

Biernacki  demonstrated  a  considerable  diminuton  of  P2O5  iu  anemia,  and 
at  the  same  time  a  certain  parallelism  between  P2O5  and  K  in  these  condi- 
tions. In  leukemia,  Freund  and  Obermayer  found  an  increase  in  P2O5,  and 
Na,  while  the  K  was  diminished. 

The  alkalies  Na  and  K  are  principally  combined  with  CI  in  the 
blood,  but  Na  is  united  in  considerable  proportions  as  phosphates  and 
carbonates.  The  sodium  salts,  being  found  principally  in  the  plasma, 
are  subject  to  marked  quantitative  variations,  being  usually  increased 
in  watery  blood.  Potassium  being  located  chiefly  in  the  red  cells  is 
diminished  in  most  hydremic  conditions,  and  not  alone  in  scurvy  as 
suggested  by  Garrod.  Sodium  carbonate  is  probably  the  next  most 
abundant  salt  of  the  plasma  after  sodium  chloride,  and  to  this  salt 
mainly  the  plasma  owes  its  alkalinity  and  its  power  to  absorb  CO2. 

Iron. — The  iron  of  the  blood  is  principally  found  in  the  hemoglo- 
bin, a  compound  of  albumen  and  iron  containing,  in  human  blood, 
about  .42  percent  of  iron.  It  also  occurs  in  traces  in  the  plasma, 
and  is  found  in  relatively  large  proportion  in  nuclein.  (Hammarsten.) 
The  percentage  of  iron  in  normal  blood  is  placed  by  Limbeck,  from 
the  results  of  several  analyses,  between  .056-.058.  Jolles  found  vari- 
ations between  .0413-.0559  percent  and  Hladik  an  average  of  .0425 
percent,  using  the  ferrometer  devised  by  the  former. 

While  the  principal  depot  of  iron  is  in  the  Hb  of  the  red  cells,  and  the 
quantity  of  iron  is  closely  propjortionate  to  the  percentage  of  Hb,  the 
ratio  between  the  tivo  is  often  disturbed,  because  all  iron  of  the  blood  does 
not  form  colored  compounds.  A  further  discrepancy  between  the  Hb 
percent  (after  Fleischl)  and  the  iron  content  of  the  blood  results 
from  the  presence  of  iron-free  pigments,  as  the  lutein  of  Thudicum  or 
the  hydrobilirubin  of  Maly. 

Thus  Biernacki  found  that  direct  quantitative  estimation  always  yields 
more  iron  than  the  computation  from  the  percentage  of  Hb,  after  Fleischl. 
Sometimes  twice  as  much  iron  was  found  as  was  to  be  expected  from  the  Hb 
percentage.  Similar  results  have  been  obtained  by  Jolles  and  Jellinek.  It 
seems  probable  that  the  genei'al  introduction  of  a  practical  clinical  method 
of  estimating  the  iron  of  the  blood  may  develop  some  new  facts  of  interest 
in  the  pathology  of  the  blood.  Thus  Jellinek  found  in  a  case  of  purpura 
Jiemorrhagica  that  iron-free  pigment  was  apparently  absorbed  from  extrava- 
sations, since  the  Hb  registered  50  percent,  after  Fleischl,  but  only  38  per- 
cent as  computed  from  the  iron-content.  Also  in  a  case  of  malaria,  imme- 
diately after  a  paroxysm  the  Hb  sank  10  percent,  while  the  iron  remained 
constant. 

Estimation  of  the  Inorganic  Principles  of  the  Blood. — It  falls  outside 
the  scope  of  the  present  volume  to  consider  the  details  of  inorganic 
quantitative  analysis  of  the  blood. 

For  the  estimation  of  Fe,  however,  reference  should  be  made  to  the 
clinical  method  and  results  of  Jolles.  This  method  permits  the  esti- 
mation of  Fe  within  15  minutes,  and  with  considerable  accuracy.  The 
apparatus  is  offered  by  Reichert's  agents  in  this  country  and  is  accom- 
panied by  full  directions  for  use. 

Mackie  has  described  clinical  methods  of  estimating  Fe,  and  phos- 


68  CHEMISTRY  OF  THE  BLOOD. 

phoric  acid,  in  a  drop  of  blood,  to  which  the  reader  is  referred.  (Iron, 
Lancet,  1898,  Vol.  I.,  p.  219  ;  Phosphoric  Acid,  Lancet,  1899,  Vol. 
IL,  p.  484.) 

Urea  in  the  Blood. 

Urea  occurs  in  traces  in  normal  blood  (Picard)  and  in  increased 
quantity  in  fevers  (Gscheidlen),  and  when,  as  in  nephritis,  its  excretion 
by  the  kidneys  is  imperfect.  In  uremia  Munzer  found  .4  percent 
of  urea  in  the  blood,  but  the  amount  is  regarded  as  insufficient  to 
cause  the  toxic  symptoms  of  this  condition. 

Demonstration  of  Urea  in  Blood.— v.  Jaksch  recommends  the  following 
procedure.  200-300  cc.  of  blood  are  precipitated  with  3-4  times  as  much 
alcohol,  and  after  24  hours  the  precipitate  is  repeatedly  washed  in  alcohol. 
The  alcohol  is  then  evaporated,  the  residue  treated  with  nitric  acid,  and  the 
crystalline  mass,  secured  after  some  hours,  is  dried  between  filter  paper, 
dissolved  in  water,  treated  with  barium  carbonate  till  CO2  ceases  to  form, 
dried  on  a  water-bath,  and  extracted  with  hot  alcohol.  On  evaporation 
urea  is  found  in  slender  rhombic  prisms.  If  secured  in  sufficient  quantity 
the  crystals  may  be  treated  with  nitric  acid  and  evaporated,  when  charac- 
teristic crystals  of  urea  nitrate  form.  Or  the  biuret  test  may  be  employed, 
dissolving  the  crystals  in  a  little  caustic  potash,  and  adding  a  drop  of  dilute 
cupric  sulphate. 

Various  other  methods  may  be  found  described  in  text-books  of  physio- 
logical chemistry,  e.  g.,  Gamgee. 

Uric  Acid  in  the  Blood. 

Scanty  traces  of  uric  acid  have  been  demonstrated  in  normal  blood. 
(Picard,  Abeles.)  Garrod  found  .025-.  145  percent  during  acute 
attacks  of  gout,  and  Salomon  also  found  an  increase  in  acute  gout. 
V.  Jaksch  regards  their  methods  as  inexact.  A  moderate  increase 
(.08  percent)  has  been  demonstrated  in  pneumonia  and  anemia  (Sal- 
omon,^ v.  Jaksch  ^),  in  cardiac  and  other  forms  of  dyspnoea,  and  in 
nephritis  (v.  Jaksch).  Klemperer  ^  and  Weintraud  noted  moderate 
increase  in  leukemia  (.09  percent),  in  nephritis  (.06  percent),  and 
in  uremia  (.19  percent),  but  failed  to  find  any  trace  in  three  healthy 
subjects  and  in  one  case  of  pneumonia. 

Estimation  of  Uric  Acid. — Garrod  took  10  cc.  of  serum  from  30-35  cc.  of 
coagulated  blood,  added  10  percent  of  dilute  acetic  acid,  and  obtained 
crystals  of  uric  acid  on  a  thread  placed  in  the  fluid.  In  blood  containing 
not  less  than  .025  per  1,000  of  uric  acid  the  thread  was  covered  with  crystals 
in  24-48  hours.     These  crystals  should  be  submitted  to  the  murexide  test. 

V.  Jaksch  recommends  the  qualitative  and  quantitative  estimation  of  uric 
acid  by  means  of  the  Ludwig-Salkowski  method  employed  in  urinary  anal- 
ysis. The  blood  is  prepared  for  this  method  as  follows  :  100-300  cc  of 
blood  are  diluted  3-4  times  with  water,  heated  on  the  water  bath  till  coagu- 
lation begins,  when  it  is  feebly  acidified  by  acetic  acid  (s.  g.  1.0335).  After 
15-20  minutes  it  is  filtered,  the  precipitate  washed  with  hot  water,  boiled 
again  after  feebly  acidifying,  cooled  and  filtered.  A  little  sodium  phos|»hate 
is  now  added  to  the  filtrate,  which  is  then  submitted  to  the  Ludwig-Salkow- 
ski method.  For  a  full  description  of  this  method  see  Simon  "  Clinical  Di- 
agnosis." 


GLYCOGEN  IN  THE  BLOOD.  69 

Glucose  in  the  Blood. 

Normal  blood  always  contains  traces  of  glucose,  which  may  be  in- 
creased by  diet  rich  in  carbohydrates,  and  is  diminished  by  muscular 
exercise  and  hunger.  (Seegen,  Chauveau  and  Cavazanni,  v.  Mering.) 
Limbeck  found  in  the  blood  of  two  healthy  subjects,  five  hours  after 
eating,  .075  pei'cent  and  .089  percent  of  glucose.  Freund  and 
Trinkler  find  that  glucose  is  very  considerably  increased  in  the  blood 
in  cases  of  carcinoma,  readily  reducing  cupric  oxide  when  freed  from 
albumens,  which  cannot  be  accomplished  with  the  blood  of  any  other 
disease  except  diabetes.  In  one  case  of  cancerous  cachexia  Trinkler 
found  .3  percent  of  glucose,  which  reaches  the  limit  stated  by  Claude 
Bernard  to  be  capable  of  producing  diuresis. 

In  diabetes  the  quantity  of  glucose  in  the  blood  is  subject  to  great 
variations,  according  to  the  character  and  progress  of  the  disease. 
Hoppe-Seyler  found  in  one  case  .9  percent. 

Estimation  of  Glucose  in  the  Blood. — A  weighed  quantity  of  blood  is 
freed  from  albumeu  by  boiling  with  an  equal  quantity  of  sodium  sulphate 
and  filtering.  The  precipitate  is  well  washed  and  the  presence  and  quantity 
of  glucose  in  the  filtrate  determined  by  Fehling's  solution  or  by  polarimetry. 
A  certain  amount  of  sugar  is  carried  away  by  the  precipitated  albumens,  and 
unless  the  blood  is  fresh,  the  action  of  the  glycolytic  ferment  may  cause 
serious  error  in  the  result. 

The  presence  of  a  glycolytic  property  in  normal  blood  has  long  been 
known,  but  it  has  never  been  shown  on  what  this  property  depends. 
Lepine  found  that  it  depended  upon  the  red  cells  more  than  upon  the 
plasma,  and  based  upon  its  presence  a  theory  that  diabetes  results  from 
the  diminution  or  absence  of  this  glycolytic  property  or  ferment.  It 
has  been  shown,  however,  that  the  glycolytic  power  of  diabetic  blood 
is  not  distinctly  inferior  to  that  of  normal  blood.  (Minkowski,  Kraus.) 
The  experiments  of  Seegen  and  of  Arthus  indicate  that  this  property  is 
not  exerted  during  life,  but  is  a  cadaveric  phenomenon,  and  that  the 
extent  of  its  action  depends  upon  the  length  of  time  consumed  in  the 
examination  of  the  specimen. 

Glycogen  in  the  Blood. 

The  long  discussion  regarding  the  feasibility  of  demonstrating  gly- 
cogen in  the  blood  by  chemical  methods  has  led  to  many  contrary 
opinions  but  in  recent  years  positive  results  have  been  more  constant. 
(Salomon,  Frerichs,  Cramer,  Lepine  and  Barral,  Huppert,  Czerny.) 

The  microscopical  test  on  specimens  dried  in  the  air  and  stained  by 
iodine,  after  Ehrlich's  suggestion,  has  given  more  uniform  results. 
Gabritschewsky,  using  this  method,  found  intra-  and  extra-cellular  gly- 
cogen in  the  blood  of  both  healthy  and  diseased  persons.  Extra-cel- 
lular glycogen,  in  the  form  of  fine  or  coarse  granules  (1-6/^.)  he  found 
to  be  the  only  form  usually  present  in  normal  blood  ;  and  it  was  increased 
in  diseases  in  which  intra-cellular  glycogen  was  abundantly  present. 
He  states  that  extra-cellular  glycogen  is  derived  from  the  disintegra- 


70  CHEMISTRY  OF  THE  BLOOD. 

tion  of  leucocytes,  but  offers  no  evidence  to  prove  this  very  unlikely 
orio-in.  The  glycogen  was  found  in  the  bodies  of  neutrophile  leuco- 
cy t*es  in  cases  of  diabetes  and  leukemia,  and  in  the  plasma  in  a  con- 
siderable variety  of  other  diseases.  The  results  of  his  experiments, 
injecting  sugar  and  peptone  into  the  blood  of  animals,  indicate  that  the 
leucocytes  are  capable  of  transforming  both  sugar  and  peptone  into 
glycogen,  Livierato  also  found  extra-cellular  glycogen  in  normal 
blood  but  failed  to  discover  any  in  the  leucocytes  in  diabetes.  From 
his  clinical  observations  he  concludes  that  the  glycogen  of  the  blood  is 
increased  in  febrile  cases  with  an  active  exudative  lesion  and  with 
leucocytosis.     In  typhoid  fever  he  found  only  extra-cellular  glycogen. 

Czerny's  studies  added  considerably  to  the  knowledge  of  the  subject.  He 
found  the  increase  of  glycogen  in  exudative  processes  with  leucocytosis. 
In  the  blood  of  children  with  cachectic  leucocytosis  he  found  an  almost 
equal  quantity.  In  2  or  3  dogs  exposed  to  prolonged  cold  he  found  that 
glycogen  appeared  in  the  leucocytes  after  24  hours,  and  persisted  for  several 
days.  From  the  severe  disturbances  of  respiration  following  section  of  both 
vagi,  or  pneumothorax  artificially  induced,  as  well  as  in  severe  anemia  from 
hemorrhage,  he  found  a  marked  increase  in  glycogen.  An  interesting  in- 
quiry of  Czerny's  related  to  the  exact  chemical  nature  of  the  brown  staining 
granules  demonstrated  by  iodine,  a  reaction  common  to  both  glycogen  and 
amyloid.  That  these  brown  granules  are  glycogen  is  indicated  by  (1)  their 
reaction  to  iodine,  (2)  by  the  disappearance  of  their  brownish  stain  on  heating 
(Barfurth),  and  (3)  by  their  complete  digestion  by  saliva.  (Czerny.)  On  the 
other  hand,  Czerny  points  out  that  pure  glycogen  is  soluble  in  water,  while 
the  glycogen  of  leucocytes  is  insoluble  in  water  (as  the  writer,  also,  has 
found),  that  iodine  with  dilute  sulphuric  acid  colors  these  granules  violet, 
which  is  the  reaction  of  amyloid  ;  and  finally  that  in  dogs  suffering  from 
prolonged  suppuration  whose  blood  continually  shows  abundance  of  "  gly- 
cogen," the  viscera,  on  the  other  hand,  develop  extensive  amyloid  changes. 
These  observations  indicate  that  the  brownish  staining  granules  are  not  pure 
glycogen^  but  a  comparatively  insoluble  compound  of  glycogen  with  some 
other  substance,  or  else  an  intermediate  product  between  glycogen  and 
amyloid. 

Caminer  failed  to  find  any  glycogen  in  normal  blood,  and  in  disease  very 
rarely  found  it  in  the  plasma.  He  distinguished  three  stages  of  the  deposit 
in  leucocytes,  (1)  the  presence  of  a  light  diffuse  mahogany  stain  ;  (2)  the 
pi-esence  of  a  few  isolated  globules  ;  (3)  the  complete  transformation  of  the 
body  of  the  cell  into  glycogen.  In  cases  of  extreme  sepsis,  all  stages  were 
seen  ;  in  pneumonia  glycogen  was  usually  present  but  never  in  the  third 
stage  of  its  formation  ;  in  phthisis  only  the  first  stage  was  found  ;  and  in 
rheumatism  it  was  absent.  In  cases  of  carcinoma  it  was  found  only  when 
suppuration  occurred.  In  four  diabetics  none  was  found,  but  in  a  case  of 
diabetic  coma  it  was  abundant.  It  was  absent  in  most  cases  of  carcinoma, 
in  chlorosis,  in  two  cases  of  leukemia  and  in  secondary  anemia  from  hemor- 
rhage. From  experimental  studies,  he  finds  that  three  factors  are  concerned 
in  the  glycogenic  degeneration  of  leucocytes  :  (1)  fever,  (2)  leucocytosis,  (3) 
toxemia,  of  which  the  last  is  most  potent. 

Further  studies  are  required  to  reconcile  the  above  conflicting  ob- 
servations and  to  establish  the  clinical  importance  of  this  form  of  de- 
generation of  leucocytes.  The  frequent  presence  of  extra-cellular  gly- 
cogen must  at  present  be  doubted,  and  it  must  be  remembered  that 
other  principles  such  as  myelin,  lecithin,  and  amyloid,  stain  brown 
with  iodine. 


ACETONEMIA.     LIPACIDEMIA.  71 

The  Diastatic  Ferment  of  the  Blood. 

The  study  of  the  property  of  fresh  blood  to  digest  starch  has  lately 
been  extended  to  the  blood  iu  various  diseases.  This  property  may  be 
demonstrated  by  adding  1  cc.  of  blood  to  50  cc.  of  a  solution  of  starch, 
allowing  the  mixture  to  stand  a  few  hours  in  the  thermostat,  when 
glucose  may  be  demonstrated  by  Fehling's  solution. 

Castellino  aud  Pracca  found  that  2  cc.  of  normal  human  blood  added  to 
50  cc.  of  starch  solution  produced  .07  percent  of  sugar  iu  twenty-four  hours, 
at  30°  C.  Arterial  blood  is  more  active  than  venous,  and  the  fermentation, 
most  active  between  30-38°  C,  is  inhibited  at  75°  C,  and  diminished  by 
slight  changes  in  reaction.  (Cavazzani.)  Cavazzaui  and  Pracca  found  con- 
siderably increased  fermentative  power  of  the  blood  in  anemia,  chlorosis, 
leukemia,  pneumonia,  malaria,  nephritis,  cirrhosis,  and  carcinoma,  while  in 
other  cases  of  these  and  other  diseases  it  was  diminished. 

The  principal  source  of  the  diastatic  ferment  is  placed  in  the  red 
cells  by  Tiegel  and  Plosz,  in  the  serum  by  Bial,  and  in  the  leucocytes 
by  Castellino  and  Pracca.  The  last  named  observers  find  that  the 
diastatic  property  is  closely  related  to  the  globulicidal  and  coagulative 
power  of  the  blood,  that  it  increases  after  the  blood  is  shed,  that  it  is 
inhibited  by  the  addition  of  nucleiu,  and  increased  by  sodium  sulphate 
and  chloride. 

Lipemia. 

The  occurrence  of  free  fat  (palmitin,  stearin,  olein)  in  the  blood, 
both  in  health  and  in  disease,  has  repeatedly  been  observed.  While 
usually  present  in  such  small  quantity  as  to  be  recovered  in  very  small 
amounts  from  the  ethereal  extract,  and  recognized  with  difficulty  by 
the  microscope,  it  is  sometimes  so  abundant  as  to  give  the  blood  a 
milky  appearance.  (Gumprecht.)  Its  physiological  variations  probably 
exceed  the  pathological,  as  it  has  been  found  very  much  increased  in 
healthy  individuals  after  a  hearty  meal.  In  disease  its  occurrence  ap- 
pears to  follow  no  general  rule,  so  that  its  real  pathological  significance 
remains  doubtful,  v.  Jaksch,  extracting  the  blood  with  ether  and 
thereby  including  fat,  lecithin,  cholesterin,  and  a  trace  of  nitrogenous 
compounds,  found  in  three  cases  of  diabetes  .05— .16  percent,  in  ne- 
phritis .1— .5  percent,  in  typhoid  fever  .16  percent,  and  in  pneumonia 
.15  percent.  It  has  also  been  found  in  increased  quantity  in  phthisis, 
poisoning  by  carbonic  oxide,  and  in  fat  embolism  after  traumatism. 
The  presence  in  the  blood  of  a  fat-splitting  ferment  (lipase)  has  re- 
cently been  claimed  by  Hanriot. 

Acetonemia.     Lipacidemia. 

Deichmuller  and  v.  Jaksch,  by  extracting  the  blood  with  ether  and 
by  distillation,  have  isolated  a  principle  which  gives  the  reaction  of 
acetone,  and  which  they  found  increased  in  many  processes,  especially 
in  fevers.  Fatty  acids  have  been  found  in  the  blood  by  v.  Jaksch,  in 
diabetic  coma,  leukemia,  acute  yellow  atrophy  of  liver,  and  acute  in- 


72  CHEMISTRY  OF  THE  BLOOD.  \ 

fectious  diseases  :  /9-oxybutyric  acid,  in  the  cadaveric  blood  of  diabetes, 
by  Hougounenq;  and  sarcolactic  acid,  in  normal  blood,  by  Gaglio, 
Spiro,  and  Berlinerblau.  Limbeck  doubts  the  reliability  of  these  re- 
sults, believing  that  fatty  acids  may  develop  from  lecithin  during  the 
technical  procedures  followed  in  isolating  these  principles. 

Cholemia. 

The  poisonous  symptoms  developed  in  cholemia  have  been  referred 
by  most  authorities  to  the  presence  of  biliary  acids.  Flint's  statement 
that  cholesterin  is  the  poisonous  agent  has  not  been  accepted,  although 
it  has  been  found  in  considerable  traces  in  icteric  blood. 

To  the  naked  eye,  icteric  blood  may  appear  of  yellowish-red  color, 
while  in  the  serum  or  its  foam  small  quantities  of  bile  pigment  are 
readily  detected  by  the  peculiar  yellowish  tinge.  On  repeated  heating 
the  yellowish-red  bilirubin  changes  to  the  green  biliverdin. 

Diminished  isotonic  tension  and  increased  resistance  of  the  red  cells 
are  a  peculiar  character  of  the  blood  in  jaundice.  Limbeck  found  the 
tension  of  the  cells  reduced  to  .4,  .38  and  .32  percent  NaCl,  and  that 
of  the  serum,  .76,  and  .864  percent  NaCl.  The  well-attested  fact 
that  in  intense  jaundice  red  cells  are  frequently  dissolved  by  biliary 
principles,  can,  with  some  difficulty,  be  reconciled  with  this  markedly 
hyperisotonic  quality  of  the  serum.  Limbeck  believes  that  bile-acids 
affect  the  union  of  Hb  with  the  stroma  of  the  red  cells,  rendering  the 
Hb  more  easily  soluble,  and  thinks  that  the  solution  of  red  cells  in 
jaundice,  as  well  as  in  other  conditions,  depends  on  other  than  simple 
osmotic  factors. 

Other  characters  of  icteric  blood  are,  according  to  Limbeck's  analy- 
ses, an  increase  of  nitrogenous  bodies  (3.29,  3.52  percent) ;  diminu- 
tion of  chlorides  of  both  blood  and  serum,  which  he  refers  to  their 
displacement  by  biliary  acids ;  and  a  well-marked  increase  in  the  vol- 
ume of  red  cells  (Bleibtreu's  method). 

Detection  of  Biliary  Principles  in  the  Blood. — Well-marked  cholemia 
may  be  detected  by  naked  eye  inspection  of  serum  or  its  foam.  On 
heating  to  50°  C.  bilirubin  may  be  changed  to  biliverdin. 

V.  Jaksch  has  been  able  to  demonstrate  bilirubin  in  the  blood  when  none 
was  to  be  found  in  the  urine,  or  when  only  urobilin  existed  in  the  urine,  by 
the  following  procedure.  A  little  blood  obtained  by  a  wet-cup  is  allowed 
to  coagulate  and  after  one  to  two  hours  the  serum  is  drawn  off  and  forced  by 
aspiration  through  an  asbestos  filter.  The  broth  of  the  filtrate  is  yellow  if 
any  bilirubin  is  present  and  this  yellow  tinge  becomes  green  on  heating  two 
or  three  hours  at  35°  C,  if  only  minute  traces  of  bile  pigment  are  present. 
Or  the  blood  may  be  coagulated  slowly  at  78-80°  C.  when  the  serum  be- 
comes greenish  in  the  presence  of  minute  traces  of  bile. 

Biliary  Acids  may  be  demonstrated  by  Pettenkofer's  method  on 
serum  prepared  as  follows  : 

Albumens  are  removed  by  boiling  or  by  alcohol,  and  the  filtrate  is  treated 
with  lead  acetate,  and  with  ammonia,  which  precipitates  the  acids  with  the 
lead  compounds.     The  acids  are  then  recovered,  by  washing  the  precipitate 


THE  SPECIFIC  GRAVITY  OF  THE  BLOOD.  73 

on  a  filter,  boiling  in  alcohol,  filtering,  and  decomposing  the  lead  salts  by 
carbonate  of  soda.  The  solution  is  again  filtered,  evaporated  to  dryness  and 
the  acids  extracted  by  boiling  in  absolute  alcohol.  Finally  on  evaporating 
the  alcoholic  extract,  biliary  acids  crystallize  out,  or  an  amorphous  substance 
remains  from  which  the  crystals  may  be  obtained  by  extracting  with  ether. 

THE    SPECIFIC    GRAVITY    OF    THE    BLOOD. 

The  specific  gravity  of  the  blood  changes  with  the  content  of  water, 
its  most  variable  constituent,  the  proportion  of  salts,  which  are  less 
variable,  and  the  percentage  of  albumens,  which  are  the  last  principle 
affected  by  pathological  processes. 

The  normal  limits  have  been  placed  by  Becquerel  and  Rodier  between 
1.058-1.062  for  men,  1.054-1.060,  including  both  sexes;  by  Ham- 
merschlag,  between  1.056-1.063,  including  both  sexes  ;  by  Lloyd  Jones, 
between  1.045-1.066.  Some  of  these  discrepancies  are  doubtless  refer- 
able to  the  differences  between  the  methods  employed. 

There  are  considerable  physiological  variations  in  gravity.  Accord- 
ing to  Lloyd  Jones  the  blood  of  newborn  infants  shows  the  highest 
gravity,  averaging  1.066  ;  after  the  second  week  of  life  up  to  the 
second  year,  the  gravity  sinks,  1.048-1.050  ;  rising  with  men  between 
35-45  years,  to  1.058,  with  women  after  the  climacteric,  to  1.054; 
in  old  age  the  blood  of  both  sexes  approaches  the  initial  high  gravity 
of  infancy.  Limbeck  finds  an  explanation  of  these  progressive  changes 
in  the  decreasing  capacity  of  the  tissues  to  absorb  water.  From  44 
estimations  on  his  own  blood  Schmaltz  found  minimal  variations  at 
diferent  hours  of  the  day,  from  1.061  from  7-8  A.  M.,  to  1.058,  from 
2-8  P.  M.  Muntz  found  a  marked  increase,  1.038  to  1.058  in  the 
gravity  of  the  blood  in  over-fed  sheep.  Muscular  activity,  if  accom- 
panied by  sweating,  slightly  decreases,  sleep  slightly  increases  the 
gravity.  (Schmaltz,  Jones.)  Schmaltz  found  that  menstruation  is 
followed  by  a  slight  increase  of  gravity,  while  the  slightly  lower 
gravity  of  pregnant  and  parturient  women  has  been  frequently 
observed. 

For  somewhat  obscure  reasons,  the  gravity  of  the  blood  is  increased 
by  residence  in  high  altitudes  and  a  considerable  difference  (.015)  has 
been  observed  in  the  blood  of  animals  pastured  on  mountain  tops  and 
those  grazing  in  the  valleys.     (Muntz,  Viault,  Glogner.) 

In  pathological  conditions  lowered  specific  gravity  is  a  constant 
character  of  the  blood  in  anemia. 

In  chlorosis  the  change  is  usually  referable  to  and  proportionate 
with  the  loss  of  Hb,  but  Stintzing  and  Gumprecht  and  Siegel  have 
shown  that  this  parallelism  is  not  invariable.  In  pernicious  anemia 
the  specific  gravity  and  dry  residue  suffer  more  than  the  Hb,  owing  to 
loss  of  albumens  from  the  serum.  Extremely  low  gravity,  in  com- 
parison with  the  Hb-content,  is  characteristic  of  this  condition.  In 
leukemia  the  gravity  is  reduced  as  in  simple  anemia,  but  extreme  re- 
ductions are  seldom  observed,  owing  to  the  increase  of  white  cells  and 
the  presence  of  abnormal  products  soluble  in  the  plasma.     In  second- 


74  CHEMISTRY  01   THE  BLOOD. 

ary  anemias  there  are  numerous  exceptions  to  the  parallelism  between 
specific  gravity  and  Hb-content.  These  are  found  especially  in  dis- 
eases in  which  an  exudative  process  drains  the  blood  of  albumens 
(dysentery),  or  when  from  edema  there  is  relative  hydremia  of  serum 
or  red  cells. 

In  the  infectious  diseases  the  specific  gravity  of  the  blood  depends 
upon  associated  conditions,  such  as  profuse  perspiration,  diarrhea,  ex- 
udation, etc.,  more  than  upon  any  specific  property  of  bacteria  to  in- 
crease the  water  of  the  blood.  That  the  power  to  impoverish  the 
blood  varies  however  with  different  infectious  agents  is  strongly  in- 
dicated by  clinical  observation.  Grawitz'  claim  that  tuberculin  and 
the  diphtheria  toxin  tend  to  increase  the  gravity  of  the  blood,  while 
the  toxines  of  streptococcus  and  staphylococcus  pyogenes  tend  to  diminish 
it,  is  frequently  confirmed  by  comparison  of  the  blood  in  cases  of  mili- 
ary tuberculosis  and  uncomplicated  diphtheria  with  that  of  septicemia. 

Although  acute  stasis  is  usually  followed  by  marked  increase  in  the 
gravity  of  the  blood,  yet  in  chronic  endocarditis  the  variations  observed 
are  very  irregular.  General  edema  is  usually  associated  with  lowered 
gravity. 

The  same  observation  applies  to  the  blood  of  nephritis^  normal 
gravity  being  observed  in  many  cases  of  chronic  interstitial  nephritis 
(Hammerschlag),  while  anemia  and  low  gravity  of  the  blood  and 
edema  of  the  tissues  are  nearly  constantly  associated  with  the  large 
white  kidney. 

Numerous  studies  of  the  blood  of  pulmonary  tuberculosis,  including 
that  of  Grawitz,  have  failed  to  bring  to  light  any  uniform  variations 
in  gravity  peculiar  to  the  blood  in  this  disease.  As  a  rule  extreme 
reductions  are  not  observed. 

In  the  cachexia  of  malignant  neoplasms  some  of  the  lowest  gravities 
on  record  have  been  observed  (1.030,  1.032,  Lyonnet),  especially  in 
ulcerating  and  bleeding  tumors  of  the  stomach  and  uterus. 

In  certain  skin  diseases  (pemphigus,  eczema,  psoriasis,  prurigo,  mor- 
bus maculosus)  an  increased  gravity  of  the  blood  has  been  noted  by 
Schlesinger.  In  cases  of  general  burns  Tappeiner,  Baraduc,  and 
Schlesinger  have  found  very  high  gravities,  1.065-1.073,  which,  in 
cases  that  recovered,  fell  to  normal  in  twenty-four  hours. 

Finally,  various  drugs  appear  to  exert  a  moderate  but  in  no  sense 
peculiar  influence  on  the  gravity  of  the  blood.  Purges,  diaphoretics, 
and  diuretics,  remove  water  from  the  system,  and  when  this  loss  is 
not  immediately  replaced  from  the  tissue  the  blood  is  temporarily  con- 
centrated. The  action  of  mercury  is  somewhat  uncertain,  but  in 
syphilis  it  appears  to  diminish  the  gravity  after  a  short  initial  period 
of  increase.     (Schlesinger.) 

To  recapitulate,  it  has  been  found  that  considerable  variations  in  the 
water  of  the  blood  may  under  ordinary  conditions  be  promptly  equal- 
ized by  the  action  of  the  tissues  on  the  one  hand  replacing  a  loss,  or 
of  the  kidneys  and  skin  removing  an  excess,  so  that  the  change  in  the 
blood  is  very  transitory.     Only  when  there  is  interference  with  these 


THE  OSMOTIC  RELATIONS  OF  THE  BLOOD.  75 

processes  or  wheu  the  demands  upon  them  are  excessive  does  a  more 
or  less  permanent  alteration  in  the  gravity  of  the  blood  follow. 

On  the  other  hand,  when  the  albumens  of  the  blood  are  affected, 
more  marked  and  permanent  changes  are  produced.  In  general,  the 
content  of  the  tissues  in  water  and  that  of  the  blood  are  very  closely 
interdependent. 

THE   OSMOTIC   RELATIONS   OF   THE    BLOOD. 

AVhen  a  drop  of  blood  is  placed  in  distilled  water,  the  red  cells  arc 
promptly  dissolved,  but  when  blood  is  placed  in  a  solution  of  salt  of 
a  certain  concentration,  the  red  cells  retain  their  Hb  and  sink  to  the 
bottom  of  the  fluid.  The  solution  of  the  cells  results  from  the  law  of  os- 
mosis, that  when  two  solutions  of  different  concentration  are  separated 
by  an  animal  membrane  the  solutions  pass  through  the  membrane, 
until  the  quantity  of  salt  in  each  is  equal.  The  force  which  leads  to 
this  interchange  is  called  "  osmotic  tension,"  and  two  fluids  with  equal 
content  of  salt  are  said  to  be  "  isotonic  "  or  of  equal  "  isotonic  tension." 
Fluids  are  likewise  said  to  be  hyper  isotonic  or  hypisotonic  when  they 
contain  greater  or  lesser  quantities  of  diffusible  salts  than  other  fluids, 
and  are  capable  of  drawing  water  from  or  yielding  it  to  such  fluids, 
according  to  the  laws  of  osmosis. 

A  solution  containing  .46  percent  of  NaCl  is  just  sufficient  to  prevent 
the  solution  of  red  cells  in  the  average  specimen  of  normal  human  blood 
(Limbeck),  and  the  isotonic  tension  of  human  red  cells  may,  therefore,  be 
said  to  be  .4.6  percent  NaCl.  Yet  Avhen  red  cells  are  placed  in  a  .46- 
percent  solution  of  salt,  they  absorb  water  and  swell,  although  they 
do  not  yield  up  Hb,  and  when  placed  in  strong  solutions  of  salt,  red 
cells  shrink,  yielding  water  to  the  fluid.  Hamburger  finds  that  a  .9- 
percent  sohUion  of  salt  causes  neither  swelling  nor  shrinkage  of  the  red 
cells.  TJiis  solution,  therefore,  represents  the  isotonic  tension  of  the  blood 
plasma,  and  is  properly  called  the  "normal  salt  solution.'' 

Any  considerable  lowering  of  the  osmotic  tension  of  the  plasma  must 
therefore  lead  to  swelling  of  the  red  cells  and  eventually  to  their  solu- 
tion. The  hyperisotonic  quality  of  the  plasma  with  reference  to  the 
red  cells  is  a  physiological  necessity,  otherwise  the  ingestion  of  a  con- 
siderable quantity  of  water  would  cause  the  solution  of  many  red  cells. 
The  exact  limits  of  osmotic  tension  between  which  the  red  cells  suffer 
no  alterations  of  volume  are  not  known,  but  it  is  certain  that  they  are 
often  exceeded  in  pathological  conditions.  Changes  in  osmotic  tension 
which  affect  the  volume  of  the  red  cells  may  occur  not  only  in  the 
plasma  but  also  in  the  red  cells.  Thus  if  the  red  cells  in  chlorosis  are 
for  some  developmental  anomaly  deficient  in  salts  they  would  shrink 
in  plasma  of  normal  (.9  percent)  osmotic  tension,  while  normal  cells 
would  swell  in  the  watery  plasma  supplied  after  hypodermoclysis  for 
hemorrhage. 

The  isotonic  relations  of  the  blood  do  not  apparently  depend  en- 
tirely upon  the  presence  of  salts,  but  are  affected  also  by  the  presence 


76  CHEMISTRY  OF  THE  BLOOD. 

of  Other  diffusible  principles,  as  the  albumens.  Limbeck  finds  only  .2 
percent  of  salts  in  red  cells,  yet  their  isotonic  tension  is  equivalent  to 
at  least  .46  percent  NaCl. 

Hamburger  finds  that  albumens,  phosphates,  and  chlorides  behave  dif- 
ferently under  changing  osmotic  conditions.  When  a  little  acid  is  added  to 
blood,  albumens  and  phosphates  pass  from  red  cells  to  serum,  while  chlorides 
pass  from  serum  to  cells,  but  when  alkali  is  added  the  opposite  transfer  is 
induced.  Similar  physical  effects  are  produced  by  the  passage  of  oxygen 
and  carbonic  acid  through  the  blood  and  Hamburger  suggests  that  these 
factors  take  important  part  in  the  metabolic  exchanges  in  the  capillaries. 

One  of  the  chief  physiological  relations  of  isoton'iG  tension  of  the  blood  is 
its  influence  in  confining  Hb  to  the  red  cells. 

Hamburger,  who  was  one  of  the  first  to  study  this  subject,  regarded  the 
fixation  of  Hb  as  the  result  solely  of  osmosis  on  the  fluid  Hb  lying  within 
the  membrane  of  the  red  cell.  Yet  the  opinion  of  Hoppe-Seyler  that  Hb 
enters  into  chemical  or  molecular  union  with  the  stroma  of  the  red  cell,  and 
the  fact  that  the  existence  of  a  membrane  about  the  erythrocyte  has  not  been 
satisfactorily  proven  (Limbeck),  render  this  belief  uncertain.  Limbeck  offers 
evidence  to  show  that  there  are  other  than  purely  physical  influences  con- 
cerned with  this  important  function,  viz.,  the  chemical  union  of  Hb  with 
other  elements  of  the  red  cells,  and  the  influence  of  albumens  on  osmosis. 

Physiological  variations  in  isotonic  tension  of  the  blood  are  numerous. 
That  of  venous  is  slightly  higher  than  that  of  arterial  blood  (.02  per- 
cent). The  addition  of  CO,  COj,  hydrogen,  nitrogen,  arsenic,  or  a 
trace  of  acid,  increases  isotonic  tension,  while  oxygen  and  traces  of  al- 
kali diminish  it.  (Limbeck.)  In  pathological  conditions,  from  a  series 
of  fifty-four  observations  on  blood  from  venesections  Limbeck  con- 
cludes :  During  acute  infections,  especially  typhoid  fever,  erysipelas, 
and  pneumonia,  the  isotonic  tension  of  the  blood  is  frequently  much 
increased,  but  not  always  or  constantly  so.  In  general  disturbances  of 
nutrition  the  tension  of  the  blood  is  very  variable  ;  in  diabetes  and 
osteomalacia  it  was  normal,  in  leukemia  it  was  much  increased,  in 
jaundice  it  was  low,  while  in  chlorosis  it  was  low,  and  in  severe  sec- 
ondary anemia  higher  than  normal. 

In  pregnancy  and  lactation  Vicarelli  found  a  distinct  increase  in  osmotic 
tension,  i.  e.,  a  diminished  resistance  of  the  red  cells  to  water  (.6-. 66  per- 
cent NaCl).  While  Limbeck  and  Castellino  found  the  red  cells  less  resist- 
ant in  typhoid  fever,  Bianchi  and  Mariotti  found  that  experimental  injec- 
tions of  B.  typhosus  lowered  the  isotonic  tension  of  the  blood  although  filtered 
cultures  of  this  and  other  bacteria  had  the  opposite  effect.  Cavazanni  found 
that  injections  and  inunctions  of  mercury  slightly  increased  the  resistance  of 
the  red  cells. 

The  tension  of  the  serum  has  been  investigated  by  Hamburger,  using 
another  method,  who  found  no  change  after  bleeding.  Viola  and  lona, 
during  seven  hours  following  venesection,  found  a  moderate  diminu- 
tion, while  Limbeck,  in  three  portions  of  blood,  taken  at  intervals 
during  the  exsanguination  of  a  dog,  found  nearly  constant  conditions, 
and  Adler  found  little  variation  in  the  tension  of  the  serum  in  various 
diseases. 


ALKALESCENCE   OF  THE  BLOOD.  77 

It  will  thus  be  seen  that  the  knowledge  of  this  subject  is  yet  in  a 
very  rudimentary  condition,  although  its  importance  in  hematology 
invites  further  investigation. 


ALKALESCENCE  OF  THE  BLOOD. 

It  is  an  established  principle  of  physiology  that  the  capacity  of  the 
blood  to  absorb  CO2  depends  on  its  alkalescence. 

When  one  compares  the  results  of  direct  alkalimetry  obtained  by 
any  of  the  recognized  methods  with  the  proportion  of  CO^  obtained 
after  the  dissociation  of  carbonates  by  strong  acids,  marked  discrepan- 
cies are  observed.  The  volume  of  CO^  differs  greatly  from  the  degree 
of  alkalinity  obtained  by  direct  titration.  To  explain  this  fact  it  must 
be  supposed  that  certain  basic  properties  of  the  blood  are  brought  into 
action  by  alkaliraetric  methods  which  are  not  active  during  life,  or  else 
that  under  changing  conditions  of  metabolism  the  blood  is  required  to 
absorb  varying  quantities  of  CO2,  which  are  by  no  means  necessarily 
proportional  to  the  capacity  of  the  blood  to  absorb  this  element. 

Thei-e  are  good  physiological  grounds  for  supposing  that  both  of  these  con- 
ditions actually  exist.  It  is  probable  that  the  existing  methods  of  titration 
are  sensible  to  the  alkaline  carbonates  and  phosphates,  which  are  principally 
concerned  in  the  alkalinity  of  the  blood,  and,  as  well,  to  some  acid-neutral- 
izing albuminous  principles  that  are  liberated  from  plasma  and  red  cells 
during  alkalimetric  procedures.  (Limbeck  and  Steindler.)  To  what  extent 
the  phosphates  and  albumens  are  concerned  in  the  physiological  functions 
centered  in  the  alkalinity  of  the  blood  is  not  known,  but  it  has  seemed  to 
the  writer  that  the  opponents  of  the  titration  method  have  failed  to  consider 
the  possibility  that  other  important  functions  besides  that  of  absorbing  CO2 
may  depend  on  the  alkalinity  of  the  blood  {e.  g.,  fibrin  formation),  and  that 
the  results  of  the  titration  method  therefore  deserve  recognition  in  the  study 
of  the  pathology  of  the  blood. 

On  the  other  hand,  the  attempt  to  measure  the  alkalescence  of  the 
blood  by  the  volume  of  CO2  recovered  after  addition  of  acids  involves  a 
needless  confusion  of  the  problem,  as  such  estimations  include  both  the  CO2 
loosely  combined  with  Hb,  and  that  more  firmly  united  with  the  alkalies.  Yet 
the  physiological  significance  of  each  of  these  combinations  is  probably  very 
different,  the  former  representing  the  respiratory  activity  of  the  blood  and 
the  metabolic  activity  of  the  tissues,  while  the  latter  is  related  to  other  less 
definitely  known  functions.  Moreover,  it  by  no  means  follows,  as  has  been 
said,  that  the  volume  of  CO2  recovered  from  the  blood  represents  the  total 
quantity  that  the  blood  is  capable  of  absorbing,  or  is  any  indication  of  its 
acid-neutralizing  power.  Bunge  calculates  that  after  allowing  for  the 
amount  of  sodium  required  to  saturate  the  only  strong  mineral  acid  of  the 
plasma  (HCl),  there  is  enough  sodium  left  to  fix  63  volumes  percent  of  CO2 
as  carbonate  and  an  equal  additional  amount  as  bicarbonate,  which  is  far 
more  than  the  amount  of  CO2  actually  present  in  the  blood. 

Again,  the  attempt  to  estimate  the  alkalescence  of  the  blood,  considered 
from  either  the  biological  or  chemical  standpoint,  by  the  content  in  CO2,  in- 
volves several  probable  errors.  There  may,  first,  be  a  diminished  produc- 
tion of  CO2  in  the  tissues  in  pathological  conditions.  There  may  be  a 
diminished  absorption  of  CO2  by  the  blood  owing  to  chemical  changes  in  the 
tissues  or  mechanical  impediments  in  the  circulation.  Finally,  there  may 
be  simple  absorption  of  COo  uncombined  with  acid  neutralizing  principles. 


78  CHEMISTRY  OF  THE  BLOOD. 

(Schafer.)  Of  the  actual  existence  or  importance  of  these  factors  it  is,  with 
the  present  knowledge  of  physiology,  difficult  to  judge,  but  since  they  stand 
as  uncertain  quantities,  it  seems  unwise  to  rely  upon  any  such  very  indirect 
method  of  judging  of  the  alkalinity  of  the  blood. 

It  would  seem  therefore  that  both  alkalimetry  and  the  estimation  of  CO2 
furnish  important  information  in  regard  to  the  state  of  the  blood,  but 
there  are  no  good  a  priori  reasons  to  suppose  that  both  measure  the  same 
property  of  the  blood,  while  the  practical  results  obtained  positively  dis- 
prove such  a  view.  When  laked  blood  is  titrated,  a  high  degree  of  alka- 
lescence is  obtained,  as  this  method  takes  account  of  all  acid-neutralizing 
principles,  carbonates,  phosphates,  and  albumens  of  plasma  and  red  cells. 
When  serum  is  titrated,  the  acid-neutralizing  principles  of  red  cells  are  ig- 
nored, and  lower  grades  of  alkalinity  are  obtained.  When  the  CO2  is  esti- 
mated account  is  taken  only  of  the  carbonates,  but  albumens  and  phosphates 
are  ignored,  and  the  presence  of  any  dissolved  CO2  disturbs  the  computation, 
while  the  possibility  still  remains  of  accidental  variations  in  the  ratio  between 
the  CO2  actually  present  and  total  capacity  of  the  blood  to  absorb  this  acid. 

The  studies  of  the  CO^-content  of  the  blood  have  given  the  following 
chief  results,  as  summarized  by  Limbeck. 

Venous  blood  is  always  richer  than  arterial  in  CO2,  and  both  are  sub- 
ject to  minor  physiological  variations  (33.37-45.3  volumes  percent, 
Schafer,  Kraus). 

Febrile  processes  are  generally  accompanied  by  diminution  of  COg  in 
the  blood,  often  in  proportion  to  the  height  of  the  fever  (34.18-20.9 
volumes  percent,  Geppert).  This  condition,  according  to  Geppert  and 
Minkowski,  is  referable  to  the  abnormal  production  of  acid  metabolic 
principles  in  the  blood,  a  view  which  is  supported  by  Kraus  who, 
in  fevers,  along  with  a  diminution  of  CO2  (10-20  volumes  percent), 
found  an  increase  in  the  acid  principles  of  the  blood. 

In  tlie  cachexia  of  carcinoma  Limbeck  and  F.  Klemperer  found 
marked  diminution  of  the  COg  of  the  blood  (9.67—20.5  volumes  per- 
cent), but  did  not  estimate  the  acid  principles.  Similar  results  fur- 
nished by  other  observers  indicate  that  in  diabetic  coma  tiie  blood 
is  frequently  very  deficient  in  CO,.  (Minkowski,  Stadelman,  Kulz, 
Hallervorden,  Kraus.)  Yet  Kraus  in  one  case  found  a  normal  quan- 
tity. A  simultaneous  increase  in  acid  principles  has  been  demon- 
strated in  one  case  of  diabetic  coma  by  Kraus,  and  on  these  grounds 
it  has  been  concluded  by  various  authors  that  in  diabetes  there  exists 
an  acid-intoxication  probably  from  oxybutyric  and  diacetic  acids. 
Limbeck  accepts  this  view  and  concludes  from  the  various  studies  that 
in  acute  febrile  infectious  diseases,  in  cancerous  cachexia,  and  in  dia- 
betic coma,  a  diminution  in  CO2  and  an  increase  of  acid  principles  of 
the  blood  have  been  fully  demonstrated,  pointing  in  all  probability  to 
the  existence  of  an  acid-intoxication  in  these  diseases.  In  leukemia 
Kraus  ^  found  a  slight  deficiency  of  CO.,  (20.29  volumes  percent). 

From  the  direct  alkalimetry  of  the  blood  or  serum  much  less  uni- 
form results  have  been  obtained.  A  fairly  constant  normal  alkalinity 
has  been  established  with  titration  methods,  v.  Jaksch  ^  placed  the 
alkalinity  of  normal  blood  at  .26-.30  percent  NaOH  ;  Kraus,  at  .226 
percent ;  Jeffries,  at  .2  percent ;  Drouin,  at  .206  percent ;  Freudberg, 


BIBLIOGRAPHY.  79 

at  .2-. 24  percent ;  Limbeck,  .220— .256  percent.  In  laked  blood  it 
has  been  found  much  higher  by  Loewy,  .449  percent ;  by  Berend, 
.45-.5  percent.  Peiper  found  slightly  greater  alkalinity  in  the  blood 
of  women  than  in  that  of  children,  and  in  the  blood  of  men  over  that 
of  women.  A  constantly  diminished  alkalinity  in  the  blood  during 
fevers  has  been  reported  by  the  above  authors,  by  Rumpf,  and  others, 
and  in  carcinoma  (Rumpf),  anemia  (v.  Jaksch,  Peiper),  leukemia 
(Peiper,  Rumpf),  uremia,  cirrhosis,  and  osteomalacia  (v.  Jaksch).  On 
the  other  hand,  the  results  obtained  by  Loewy  and  by  Limbeck  and 
Steindler,  using  their  particular  methods,  were  extremely  variable,  and 
these  variations  were  about  equal  in  health  and  disease. 

Further  observations  are  therefore  necessary  to  determine  the  true 
significance  of  the  changes  demonstrable  by  titration  methods. 

THE   ACIDITY   OR   BASIC    CAPACITY   OF    THE   BLOOD. 

There  are  certain  unsaturated  salts  in  the  blood  (NaHCOg,  NaH^PO^ 
and  probably  Na2HPO^,  Limbeck),  which  although  alkaline  to  litmus 
are  acid  to  phenolphthalein,  and  are  capable  of  uniting  with  bases. 
While  fresh  blood  is  alkaline,  serum  reacts  as  acid  to  phenolphthalein. 
The  capacity  of  the  blood  salts  to  neutralize  bases  has  been  called  its 
basic  capacity,  by  Kraus,^  who  devised  a  delicate  and  somewhat  diffi- 
cult method  of  measuring  this  capacity. 

In  normal  venous  blood  Kraus  found  a  basic  capacity  of  .162-.232 
percent  NaOH,  which  increased  in  febrile  conditions  to  .209-.272  per- 
cent NaOH.  His  demonstration  of  a  marked  increase  of  basic  ca- 
pacity (.347  percent)  in  diabetes,  has  been  regarded  as  strong  evidence 
of  an  acid  intoxication  in  this  disease. 

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P 


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CHAPTER    III. 

MORPHOLOGY   AND    PHYSIOLOGY   OF   THE   RED 

CELLS. 

In  fresh  normal  blood  the  red  cells  appear  as  homogeneous  bicon- 
cave disc-shaped  bodies,  with  opaque  yellowish  rim  and  nearly  trans- 
parent center.  They  show  a  strong  tendency  to  cohere  to  one  another 
by  their  flat  surfaces,  forming  long  rows  (rouleaux).  This  property 
has  been  referred  to  the  presence  of  a  fatty  material  surrounding  the 
red  cells.  In  the  capillary  circulation  they  exhibit  remarkable  elas- 
ticity, folding,  indenting,  and  greatly  elongating,  without  rupture. 
After  early  infancy  they  are  invariably  non-nucleated. 

In  dry  specimens  when  thinly  spread  and  rapidly  dried  they  are  cir- 
cular in  outline,  their  concavities  are  obliterated  and  they  stain  evenly 
throughout.  When  rather  thickly  spread  the  rouleaux  are  retained, 
the  concavities  persist,  and  the  centers  may  be  nearly  transparent  while 
the  thicker  rims  are  densely  stained. 

Neither  membrane  nor  reticulum  have  been  fully  demonstrated  in  the 
human  red  blood  cell,  although  both,  from  analogy,  have  been  sup- 
posed to  exist.  It  is  more  probable  that  the  hemoglobin  is  held  in 
compact  form  by  a  chemical  union  with  other  albuminous  constituents 
of  the  cell.     (Schafer.) 

Staining  Reactions. — The  living  red  cell  is  achromatic,  but  when 
fixed,  is  markedly  acidophile  in  quality,  a  ])roperty  ])robably  residing 
exclusively  in  the  Hb.  In  the  center  of  the  cell  there  is  an  achro- 
matic constituent  which  fails  to  stain  with  acid  dyes,  but  under  some 
circumstances  this  central  substance  may  become  partially  separated 
or  even  extruded  from  the  cell,  when  it  stains  lightly  with  methylene- 
blue,  and  yields  the  specific  reaction  of  chromatin  (Nocht's  method). 

Two  views  regarding  the  structure  of  the  red  blood  cell  have  been  main- 
tained. According  to  the  first  the  red  blood  cell  is  vesicular,  consisting  of 
colored  semifluid  contents,  hemoglobin,  surrounded  by  a  membrane  and 
supported  by  a  stroma  composed  of  various  substances,  principally  lecithin, 
cholesterin,  and  cell-globulin.  (Schafer.)  According  to  the  second  view, 
the  red  cell  is  not  vesicular  but  a  viscous  solid  mass,  consisting  of  a  colorless 
elastic  stroma  v/hich  is  condensed  at  the  periphery  and  which  supports,  i»artly 
by  mechanical  means  and  partly  by  chemical  union,  the  hemoglobin  and 
other  constituents  of  the  cell.     (Rollett,  Brucke.) 

It  is  not  impossible  to  partly  reconcile  these  opposing  views,  regarding 
the  peripheral  condensation  of  stroma  as  in  many  respects  similar  to  a  mem- 
brane. That  the  cell  is  not  strictly  vesicular  with  separable  fluid  contents 
is  shown  by  the  fact  that  it  may  be  subdivided  without  escape  of  contents, 
each  fragment  assuming  the  discoidal  shape. 


PLATE    I. 


Normal    Blood.     (Triaeid  Stain.) 


Fig.  I.  Normal  red  cell,  flatly  spread,  and  evenly  stained. 

Fig.  2.  Normal  rouleau. 

Fig-  3.  Normal  red  cells,  varying  slightly  in  size,  thickly  spread,  showing  central   clear  areas. 

Fig.  4.  Normal  red  cell,  of  slightly  altered  shape. 

Fig.  5.  Lymphocyte,  medium  size. 

Fig.  6.  Large  mononuclear  leucocyte,  incurved  nucleus. 

Fig.  7.  Polynuclear  neutrophile  leucocyte. 

Fig.  8.  Eosinophile  leucocyte.     Separate  nuclear  lobes. 


I 


SIZE   OF  RED   CELLS.  83 

According  to  Foa  the  hemoglobin  is  limited  to  a  peripheral  layer  of 
(iiauules  under  which  lies  homogeneous  cell  protoplasm,  and  this  view  is  sup- 
ported by  the  occasional  escape  in  pathological  conditions  of  a  central  achro- 
matic substance  leaving  the  hemoglobin  more  or  less  intact. 

Size  of  Red  Cells. — In  normal  subjects,  the  average  diameter  of  red 
CI  lis  varies  between  7  and  8  /Jt,  depending  considerably  upon  the 
method  employed  in  preparing  the  specimen.  The  following  table 
compiled  by  Limbeck  shows  the  results  obtained  by  different  writers  : 


Limits. 


4.5-9.5  fi 


Welcker 

Valentin 

Malinin 

Hayem  6    -8 

Malassez 

Laache 6    -9 

Bizzozero  7.0-7.15 

Gram  I    6.7-9.3      1     7.7-8 


Average. 


7.2-8.1/1. 

7.0 

7.7 

7,5 

7.6 

8.5 


From  75  to  90  percent  of  the  cells  fall  within  average  diameters.  Sex 
has  no  influence  upon  the  size  of  red  cells,  and  after  infancy  the  diam- 
eters remain  constant.  In  normal  infants'  blood  the  variations  in  the 
size  of  the  cells  are  considerable,  3.3-10.3  fi.      (Hayem.) 

Ill  path^lojlc'd  coivUtion-t,  variations  in  the  size  of  red  cells  are  one 
of  the  most  important  of  morphological  features.  In  general,  varia- 
tions in  the  size  of  the  cells  indicate  a  severe  and  chronic  anemia, 
while  in  mild  and  in  very  acute  anemias,  the  diameters  are  usually 
le  altered. 

MiCROCYTES  are  cells  distinctly  under  the  normal  size  and  may 
show  a  diameter  of  4  to  1  /i. 

Several  influences  appear  to  be  concerned  in  the  formation  of  mi- 
crocytes.  It  is  probable  that  cells  poor  in  Hb,  lying  in  plasma  of  high 
gravity  and  osmotic  tension  may  be  reduced  in  size,  from  the  direct 
loss  of  substance  and  the  concentrating  influence  of  a  fluid  of  high  os- 
motic tension.  These  conditions  are  present  in  some  cases  of  chlorosis, 
but  the  attempt  to  show  that  the  cells  in  this  disease  are  uniformly 
undersized  has  not  been  successful.  Many  microcytes  probably  result 
from  the  splitting  of  portions  of  degenerating  and  ameboid  red  cells,  as 
in  pernicious  anemia.  The  occasional  occurrence  of  nucleated  red  cells 
of  small  or  minute  size  indicates  that  some  microcytes  arise  by  division 
of  undersized  mother-cells.  This  mode  of  origin  is  probably  limited 
to  pernicious  anemia. 

The  clinical  significance  of  the  presence  of  undersized  cells  or  dis- 
tinct microcytes  is  rather  indefinite.  In  some  cases  of  chlorosis  the 
cells  appear  to  be  uniformly  smaller  than  normal,  but  this  character  is 
not  invariable.  In  some  cases  of  chronic  anemia  of  pernicious  grade, 
the  majority  of  cells  are  undersized  and  deficient  in  Hb.  In  primary 
pernicious  anemia,  microcytes  with  increased  or  diminished  Hb  are 
constantly  present.  Tallquist  believes  that  the  presence  of  many  mi- 
crocytes is  an  indication  of  rapid  destruction  of  blood. 


84       MORPHOLOGY  AND  PHYSIOLOGY   OF  THE  RED  CELLS. 

Megalocytes  are  cells  distinctly  larger  than  normal.  They  usu- 
ally vary  between  10  and  20  ft  in  diameter.  Most  of  these  cells  form 
from  the  division  of  the  large  nucleated  red  cells  which  appear  in  red 
marrow  in  severe  chronic  and  especially  in  pernicious  anemia.  In 
addition  to  this  mode  of  origin  it  is  probable  that  many  slightly  en- 
larged cells  and  megalocytes  are  produced  by  the  swelling  which, 
under  the  laws  of  osmosis,  results  when  red  cells  lie  in  plasma  of  low 
gravity  and  low  osmotic  tension.  Megalocytes  may  show  an  excess  or 
a  deficiency  of  Hb,  and  frequently  exhibit  a  brownish  stain  after  eosin. 

The  presence  of  megalocytes  indicates  an  anemia  of  severe  grade 
and  usually  of  rather  long  standing.  Their  appearance  denotes 
regenerative  activity  on  the  part  of  the  blood.  (Tallquist.)  Some 
authorities  arbitrarily  suggest  that  when  megalocytes  form  more  than 
10  percent  of  the  cells  the  case  should  be  classed  as  pernicious  anemia. 
In  secondary  pernicious  anemia  the  megalocytes  are  frequently  defi- 
cient in  Hb,  while  in  primary  pernicious  anemia  they  usually  contain 
an  excess  of  this  principle. 

Nucleated  Red  Blood  Cells. — While  the  presence  of  nucleated  red 
cells  in  the  blood  at  any  period  of  extra-uterine  life  may  be  considered 
pathological,  it  must  be  admitted  that  prolonged  search  in  the  blood 
of  infants  shortly  after  birth  will  usually  disclose  the  presence  of  a 
few  of  these  cells. 

Normoblasts  are  nucleated  red  cells  of  normal  size  and  character 
(7—9  //).  They  usually  show  a  normal  or  slightly  increased  quantity 
of  hemoglobin,  fail  to  show  a  biconcave  form,  do  not  cohere  in  rouleaux, 
and  exhibit  a  central  densely  staining  spheroidal  nucleus  occupying 
one-third  of  the  diameter  of  the  cell.  Much  less  frequently  the 
nucleus  is  subdivided  into  two  or  three  lobes,  more  or  less  closely  con- 
nected, while  mitotic  figures  in  normoblasts  have  several  times  been 
described.     (Luzet,  Troje,  Askanazy.') 

Normoblasts  are  most  commonly  seen,  in  very  variable  numbers,  in 
the  milder  forms  of  anemia,  chlorosis,  acute  anemia  from  hemorrhage, 
early  leukemia,  etc.  They  may  be  very  abundant  in  the  anemia  of 
children,  especially  in  v.  Jaksch's  type.  In  severe  anemia  they  are 
usually  associated  with  larger  nucleated  red  cells.  In  children  any 
severe  disturbance  of  the  circulation,  especially  if  accompanied  by  af- 
fection of  the  bone  marrow,  may  cause  the  appearance  in  the  blood  of 
a  few  normoblasts.  Severe  leucocytosis  in  children  and  even  in  adults 
may  draw  a  few  normoblasts  into  the  circulation.  In  anemic  subjects, 
ante-mortem  leucocytosis  may  be  of  this  character.  In  chlorosis,  a 
periodical  increase  of  normoblasts,  lasting  4-6  days,  repeated  at  inter- 
vals apparently  favored  by  rest  in  bed  and  successful  medication,  and 
accompanied  by  a  marked  increase  in  red  cells,  has  been  described  by 
V.  Noorden,  under  the  term  "  blood  crisis."  This  phenomenon  chiefly 
has  given  rise  to  the  belief  that  the  appearance  of  normoblasts  is  of 
favorable  import  in  anemia.  This  opinion  may  be  accepted,  not  be- 
cause the  normoblasts  appear  in  the  circulation,  but  because  their  ap- 
pearance indicates  active  reproduction  and  discharge  of  red  discs  from 


PATIIOLOQWAL   CHANGES  IN  RED  BLOOD   CELLS.  85 

the  marrow,  and  demonstrates  that  the  type  of  blood  formation  is 
physiological. 

Megaloblasts  are  nucleated  red  cells  of  larger  than  normal  dimen- 
sions (10—20  fj.).  When  exceeding  20  /j.  in  diameter,  they  are  usually 
called  gigantoblasfs.  They  are  usually  circular  in  outline,  but  are 
readily  deformed  in  spreading.  Megaloblasts  may  show  a  deficiency  of 
hemoglobin,  but  usually  contain  an  excess,  in  which  case  they  are  apt  to 
stain  brownish  with  eosin  (polychromatophilia).  The  nuclei  of  mega- 
loblasts show  a  great  variety  of  forms.  They  may  be  found  in  :  (1) 
the  ordinary  vesicular  form  of  the  resting  stage  with  intranuclear  net- 
work and  nodal  thickenings,  but  without  nucleoli,  or  they  may  be  (2) 
pyhiomorpliotts  consisting  of  one  or  several  densely  staining  lobes, 
either  distinctly  separate  or  grouped  in  irregular  rosette  form  ;  or  (3) 
they  may  exhibit  phases  of  normal  or  pathological  mitosis,  with  irregu- 
lar wreaths  or  two  or  three  unequal  asters ;  or  (4)  they  may  show 
many  stages  of  karyorhexis,  with  fragmentation,  vacuolation,  fading  of 
segments  of  nuclei,  as  well  as  minute  subdivision  into  fine  basic  stain- 
ing particles  widely  scattered  in  the  cell.     (See  Plate  V.) 

The  significance  of  the  presence  of  megaloblasts  in  the  blood  depends  on 
the  conditions  with  which  they  are  associated. 

Megaloblasts  are  seen  in  smears  of  the  marrow  of  many  young  in- 
fants, and  when  seen  in  the  circulation  of  such  subjects  in  small  num- 
bers and  with  a  majority  of  small  nucleated  cells,  they  have  the  same 
significance  as  normoblasts.  In  cases  of  severe  anemia  of  adults  a  few 
nucleated  red  cells  of  moderately  large  dimensions  are  sometimes  seen 
with  a  larger  number  of  normoblasts,  when  no  special  significance  can 
be  attached  to  their  discovery. 

When  the  majority  of  a  considerable  number  of  nucleated  red  cells 
are  megaloblasts,  especially  if  gigantoblasts  are  present  and  unequal 
mitotic  figures  are  observed,  the  diagnosis  of  primary  pernicious 
anemia  is  justified.  The  presence  of  a  few  megaloblasts  alone  is 
usually  found  only  in  primary  pernicious  anemia,  but  may  occur  in 
pernicious  secondary  anemia.  Possibly  the  discovery  of  a  single 
gigantoblast  may  warrant  the  diagnosis  of  primary  pernicious  anemia. 

In  general,  the  appearance  of  megaloblasts  in  the  blood  indicates 
that  a  pathological  type  of  blood  formation  has  been  established  in  at 
least  a  part  of  the  red  marrow.  Whether  this  change  represents  a  re- 
version to  the  embryonal  type  of  blood  formation,  as  suggested  by 
Cohnheira,  cannot  yet  be  determined,  and  will  be  considered  later. 
Probably  the  low  osmotic  tension  of  the  watery  plasma  may  be  re- 
sponsible for  some  of  the  increased  size  of  the  nucleated  red  cells  of 
pernicious  anemia. 

Pathological  Changes  in  Red  Blood  Cells. 

Simple  loss  of  Hb  is  one  of  the  commonest  changes  occurring  in  red 
cells,  this  being  the  chief  cellular  lesion  in  chlorosis  and  mild  sec- 
ondary   anemia.      When    deficient    in   Hb    the  cell    exhibits    an    en- 


8G       MORPHOLOGY  AND  PHYSIOLOGY   OF  THE  RED   CELLS. 

kirged  central  clear  area  of  variable  outline.  In  extreme  cases  the  cell 
may  be  reduced  to  a  very  thin  ring  of  Hb,  inclosing  a  wide  and  per- 
fectly transparent  central  area.  In  dry  specimens,  such  cells  when 
thinly  spread  and  rapidly  dried  may  fail  to  exhibit  a  marked  central 
clear  area,  but  the  whole  cell  shows  a  uniform  pallor.  Occasionally 
the  central  clear  area  is  irregular,  owing  either  to  ameboid  changes  in 
the  red  cell  or  to  the  unequal  loss  of  Hb  in  different  parts  of  the  cell, 
or,  frequently,  to  artificial  influences.  Thus  may  arise  minute  clefts 
and  the  heaping  of  remnants  of  Hb  in  the  center  of  the  cell.      (Plate 

YI.) 

Poikilocytosis  is  a  term  applied  to  the  appearance  in  blood  of 
misshapen  red  cells.  Probably  the  chief  mode  of  origin  of  poikilo- 
cytes  is  through  the  effects  of  ameboid  motion  of  a  portion  or  the 
whole  of  the  cell,  which  has  been  described  as  among  the  phenomena 
occurring  in  degenerating  red  cells.  A  great  variety  of  shrunken  and 
misshapen  cells  are  produced  artificial/ ij  in  dried  specimens  of  anemic 
blood.  The  true  poikilocyte  is  usually  a  pear-shajjed  cell  with  a 
short  globular  projection  at  one  or  more  poles.  Extremely  irregular 
cells  usually  result  from  shrinkage  or  trauma.  Very  small  cells  may 
be  formed  by  the  separation  of  fragments  of  poikilocytes.     (Ehrlich.) 

Poikilocytosis  is  an  indication  of  a  severe  anemia  with  degenerative 
changes  in  the  red  cells. 

Ameboid  motion  of  entire  cells  or  of  fragments  of  cells,  or  of  central 
colorless  masses  in  necrobiotic  cells  may  be  observed,  in  slight  degree, 
in  many  severe  anemias.  This  phenomenon,  which  is  more  commonly 
observed  in  the  blood  of  the  low  vertebrates,  is  probably  respon- 
sible for  the  production  of  many  poikilocytes,  and  for  the  subdivision 
of  red  cells,  but  is  otherwise  lacking  in  special  significance.  (Cf. 
Askanazy.) 

Variations  in  size  of  red  cells  is  an  important  feature  of  degenerative 
processes  which  is  considered  elsewhere. 

In  cases  of  acute  poisoning  in  man  and  animals,  a  considerable  va- 
riety of  degenerative  changes  in  red  cells  has  been  described  by  many 
writers,  but  these  do  not  yet  admit  of  accurate  classification.  Among 
them  may  be  mentioned  :  (1)  the  liemoglobineniic  der/cneration  of  Ehrlich, 
which  consists  in  the  appearance  of  droplets  of  Hb  within  the  cell ;  (2) 
the  subdivision  of  the  cell  with  formation  of  microcytes,  as  seen  in  some 
forms  of  poisoning  (Litten)  and  after  severe  burns  ;  (3)  the  specific  re- 
action of  diabetic  blood  described  by  Bremer ;  and  (4)  the  changes  in 
color  to  be  noted  after  poisoning  by  hydrochloric  acid,  hydrocyanic 
acid,  chlorate  of  potash,  and  some  coal-tar  products. 

The  malarial  parasite  produces  a  peculiar  series  of  degenerative 
changes  in  the  red  cell  which  will  be  considered  later. 

Anemic  or  Polychromatophilic  Degeneration.  Polychromasia. 
Polychromatophilia. — Under  the  term  polychromatophilia  two  ap- 
parently distinct  conditions  have  been  described. 

The  term  is  applied  by  Ehrlich  ^  to  the  appearance,  especially  in 
cases  of  chronic  anemia,  of  cells  which,  after  hematoxylon  and  eosin. 


ANEMIC  OR  POLYCHROMATOPHILIC  DEGENERATION.  87 

instead  of  staining  light  red  take  a  bluish  red  or  violet  tinge,  or,  in 
extreme  examples,  even  take  a  deep  blue  stain.  These  various  abnor- 
mal tints  are  referred  by  Maragliano,  Castellino,  and  Ehrlich,  to  a  pro- 
gressive coagidat'ion-necrosis  of  the  cell  which  thereby  loses  its  power 
to  retain  Hb  and  gradually  yielding  this  element  to  the  plasma,  loses 
also  its  normal  affinity  for  acid  dyes.  This  opinion  is  based  on  the 
following  grounds:  (1)  The  appearance  of  cells  showing  an  advanced 
stage  of  the  change,  in  which  the  frequent  breaks  in  contour  "  convince 
every  practiced  eye  that  the  cell  is  approaching  solution."  (2)  By  the 
abundance  of  such  cells  in  starving  animals  where  new  formation  of 
red  cells  is  not  to  be  expected,  and  (3)  by  their  abundant  presence 
within  23  hours  after  hemorrhage,  when  normoblasts  are  only  excep- 
tionally seen,  and  (4)  by  the  constant  polychromatophilic  tendency  of 
megaloblasts  as  compared  with  normoblasts. 

Gabritschewsky,  Smith,  Askanazy,^  Engel,  Dunin,  and  many  others 
believe  that  polychromatophilic  discs  are  not  degenerating  hut  on  the 
contrary  are  the  youngest  red  cells  of  the  blood.  This  view  is  supported 
by  the  abundance  of  such  cells  shortly  after  severe  hemorrhages  and  in 
many  other  conditions  where  red  cells  are  being  rapidly  formed.  As- 
kanazy  found  polychromatophilia  of  all  the  nucleated  red  cells  in  the 
marrow  of  a  rib  just  after  its  excision  and  before  degenerative  changes 
could  have  set  in,  and  states  that  a  large  proportion  of  cells  in  the  liver 
of  the  seven  months'  fetus  are  polychromatophilic.  Walker  also 
found  as  high  as  34.75  percent  of  basophilous  red  cells  in  the  blood  of 
a  fetal  puppy,  while  in  the  marrow  of  various  healthy  domestic  animals 
they  varied  from  12  to  62  percent. 

Engel  has  shown  that  there  is  a  physiological  polychromasia  be- 
longing to  a  portion  of  the  red  cells  of  the  embryo,  and  Ehrlich  ^ 
accepts  this  fact  without  yielding  his  opinion  that,  in  the  adult, 
polychromasia  is  a  sign  of  degeneration.  According  to  Engel,  poly- 
chromatic cells  appear  when  rapid  new  formation  of  red  corpuscles  is 
demanded,  and  when  there  is  not  time  for  the  complete  shrinkage  of 
nucleus  and  development  of  orthochromatic  cells. 

The  bearing  of  the  first  studies  of  Maragliano  and  Castellino  is  here 
of  importance.  These  observers  found  that  normal  blood  in  carefully 
prepared  fresh  specimens  begins  to  show  distinct  alterations  of  the  red 
'cells  after  standing  10-12  hours.  These  consist  in  widening  of  the 
central  colorless  area,  appearance  of  ameboid  activity  in  this  area,  for- 
mation of  poikilocytes  and  development  of  a  basic  staining  quality  in  a 
part  or  the  whole  of  the  cell.  In  various  pathological  conditions  they 
found  these  changes  present  immediately  after  shedding  and  the  more 
rapid  their  appearance  the  graver  was  the  general  condition  of  the 
patient.  The  authors  belie  v^e  that  these  changes  may  occur  in  the  cir- 
culating blood  ;  that  they  are  referable  to  decreased  stability  of  cells 
and  increased  globulicidal  activity  of  plasma  ;  and  that  they  affi^rd  val- 
uable clinical  evidence  of  destruction  of  blood.  They  depict  cells  which 
show  the  polychromatophilic  tendency  of  Ehrlich,  and  other  cells  in 
ivhich  there  is  the  formation  of  a  central  mass  lohich  stains  bluish  by  meth- 


88       MORPHOLOGY  AND  PHYSIOLOGY  OF  THE  RED  CELLS. 

ylene-blue  ^  and  which  has  been  shown  to  herald  the  extrusion  of  a  por- 
tion of  the  red  cell  in  the  form  of  blood  plates.     (See  Plate  II.,  Fig.  2.) 

The  processes  represented  by  these  two  kinds  of  altered  cells  maybe  re- 
lated but  are  certainly  not  identical,  and  since  the  chief  evidence  in  favor 
of  the  degenerative  nature  of  Ehrlich's  polychromatophilic  cells  is  found 
in  the  studies  of  Maragliano,  it  would  seem  that  further  investigation 
is  necessary  before  one  can  accept  the  view  that  such  cells  are  necrotic. 

Finally,  it  should  be  mentioned  that  Sherrington  refers  the  brownish 
staining  reaction  frequently  seen  in  red  cells  in  severe  anemia  to  in- 
complete oxidation  of  Hb. 

To  summarize  the  evidence  in  this  field,  it  appears  that  the  term  poly- 
chromasia  should  be  limited  to  a  diffuse  brotvnish  staining  qnality  of  the 
red  cells  occurring  in  various  forms  of  anemia,  and  abundantly  in  normal 
marrow,  the  significance  of  which  is  undetermined.  The  appearance  of 
bluish  staining  granules  and  areas  in  red  cells,  often  described  under  this 
same  term,  should  be  classed  with  Graivitz'  granular  degeneration  of  red 
cells.     (Cf  Plates  Y.,  Fig.  6,  and  VI.,  Figs.  4,  5.) 

Granular  Degeneration  of  Red  Cells  (Grawitz).  Punctate  Ba- 
sophilia of  Red  Cells. — The  attention  of  pathologists  has  long  been 
attracted  by  the  presence  of  bluish  staining  granules  and  masses  in  red 
cells  and  they  have  repeatedly  been  interpreted  as  remnants  of  a 
nucleus.  In  specimens  stained  by  the  Nocht-Romanowsky  method 
these  masses  usually  give  the  reaction  of  chromatin.  Lately  the  for- 
mation and  significance  of  these  bodies  have  been  fully  considered  by 
Maximow,  who  calls  them  "  nucleoids  "  and  whose  conclusions  regard- 
ing their  nuclear  character  can  hardly  be  doubted. 

In  1893  Askanazy  ^  described  the  appearance  of  many  fine  baso- 
philic granules  in  the  bodies  of  nucleated  red  cells  in  pernicious  anemia, 
regarding  them  as  evidence  of  karyorhexis.  In  1894  Schumann  saw 
such  cells  in  the  anemia  of  hothriocephalus,  and  in  1896  Lazarus  de- 
scribed them  in  20  cases  of  pernicious  anemia,  while  failing  to  find 
them  in  other  diseases.  Later  they  were  described  in  pernicious  anemia 
and  variously  interpreted  by  Klein,  Zenoni,^  Lenoble,  and  Grawitz.^ 
Very  similar  changes  have  been  described  in  secondary  anemia,  normal 
blood,  in  birds'  blood,  and  in  that  of  the  human  embryo  by  Askanazy, 
Gabritschewsky,  Klein,  Pappenheim,  and  Engel.^  Plehn  found  them 
abundantly  in  the  blood  of  malarious  subjects  and  regarded  them  as 
remnants  of  the  parasite. 

Grawitz  has  recently  described  the  appearance  and  studied  the  nature 
and  occurrence  of  such  cells  in  human  blood,  concluding  that  they 
represent  a  specific  form  of  degeneration.  He  did  not  find  any  evi- 
dence of  increased  karyolysis  in  the  normoblasts  of  marrow  when  de- 
generating cells  were  found  in  the  blood,  except  in  very  severe  anemia. 
The  exact  origin  of  the  bluish  staining  granules  he  is  unable  to  explain, 
but  thinks  they  have  no  connection  with  a  process  of  karyolysis.  In 
pernicious  anemia  and  leukemia  Grawitz  could  always  find  many  cells 

•Ehrlich  warns  against  the  use  of  methylene-blne  in  demonstrating  polychromato- 
philia,  using  only  the  triacid  mixture,  or  heraatoxylon  and  eosin.    ( Die  Anemie,  p.  34. ) 


THE  NUMBER   OF  RED   BLOOD   CELLS.  89 

in  granular  degeneration,  but  in  11  cases  of  severe  chlorosis  they  were 
missing.  In  carcinoma  they  were  present  when  the  tumor  was  in  such 
a  situation  "  as  to  favor  the  absorption  of  toxic  substances."  Thus 
they  were  present  in  10  cases  of  gastric  and  esophageal  cancer,  but 
absent  in  two  cases  of  uterine  carcinoma.  They  were  very  abundant  in 
chronic  lead  poisoning,  as  has  also  been  noted  by  Behrendt.  They 
were  not  found  in  numerous  cases  of  tuberculosis  and  syphilis. 

The  writer  has  frequently  noted  these  changes  in  red  cells  in  per- 
nicious anemia,  and  is  convinced  that  in  megaloblasts  they  often  result 
from  karyorhexis,  having  seen  many  transitional  stages  of  the  frag- 
mentation and  fine  subdivision  of  these  nuclei.  In  the  hydremic 
blood  of  malarial  cachexia  they  are  extremely  common.  In  some 
cases,  after  overstaining  in  methylene-blue,  nearly  every  red  cell  shows 
such  bluish  points,  sometimes  connected  with  fine  threads. 

The  Numbers  of  Red  Blood  Cells. — It  is  hardly  necessary  to 
point  out  that  the  present  method  of  enumerating  the  red  cells  in  a 
unit  of  volume  of  blood  gives  an  imperfect  estimate  of  their  total 
number  in  the  body.  Yet  the  conclusions  that  are  constantly  being 
drawn  from  such  information  could  be  justified  only  in  case  there  were 
a  uniform  relation  between  the  number  of  cells  per  cubic  millimeter 
and  their  total  number  in  the  body.  The  considerations  mentioned  in 
the  Introductory  Section  show  that  in  pathological  conditions  no  such 
relation  uniforndy  exists.  On  the  other  hand,  since  the  total  quantity 
of  blood  in  healthy  subjects  is  properly  adapted  to  each  individual,  the 
bulk  is  of  less  practical  importance  than  the  proportion  in  the  unit  of 
volume,  and  the  enumeration  of  red  cells  in  tolerably  healthy  cases, 
therefore,  warrants  the  same  conclusions  that  could  be  drawn  from  the 
estimation  of  their  total  numbers  in  the  body. 

The  original  estimates  of  Welcker  (1854),  that  in  the  cubic  milli- 
meter of  blood  there  are  normally  5,000,000  red  cells  in  men  and 
4,500,000  in  women,  have  not  been  seriously  disturbed  by  many  sub- 
sequent observations  by  means  of  Malassez'  method.  Perhaps  the 
chief  contribution  of  later  observers  using  Thoma's  instrument  has  been 
the  proof  that  the  numbers  are  more  apt  to  exceed  rather  than  fall 
below  these  averages,  especially  in  men,  a  fact  that  has  become  more 
certain  from  the  more  careful  estimates  of  the  last  decade.  Thus  the 
average  obtained  bv  Helling  was  5,910,000  ;  by  Fredrichson  5,072,- 
000  fZaslein,  5,010,000 ;  Neubert,  5,603,000;  Graber,  5,081,000; 
Stierlin,  5,752,000;  Heinicke,  5,209,667;  Andriezen,  6,000,000; 
Hayem,  5,500,000. 

The  variations  in  the  number  of  red  cells  referable  to  physiological 
and  accidental  causes  are  so  numerous  and  distinct  as  to  require  their 
consideration  in  detail. 

1.  Time  of  Day. — The  variations  found  by  some  observers  at 
different  hours  of  the  day  may  probably,  as  Limbeck  suggests,  be  re- 
ferred to  the  influence  of  digestion  and  exercise.  Reinert  found  a 
tendency  toward  diminution  of  red  cells  and  increase  of  leucocytes  as 
the  day  progressed  with  healthy  subjects. 


90       MORPHOLOGY  AND  PHYSIOLOGY  OF  THE  RED  CELLS. 

2.  Digestion. — With  but  few  reports  to  the  contrary,  the  observa- 
tions of  Yierordt  and  Duperie,  Reinert,  and  Limbeck,  indicate  that 
within  one-half  to  one  hour  after  the  ingestion  of  a  full  meal  the  pro- 
portion of  red  cells  begins  to  diminish,  falling  usually  250,000-750,- 
000  per  cubic  mm.  The  numbers  diminish  for  2-4  hours  and  then 
gradually  approach  the  normal.  The  percentage  of  Hb  falls  pro- 
portionately. These  eifects  are  more  prominent  after  a  largely  fluid 
meal,  and  are  probably  referable  to  the  absorption  of  fluids  with  dilu- 
tion of  the  blood. 

For  the  same  reasons,  hunger  has  been  found  by  many  observers  to 
cause  in  animals  a  considerable  increase  in  red  cells.  (Bidder  and 
Schmidt,  Voit,  Subotin,  Panum,  Groll,  Hosslin,  Raum.) 

The  observations  on  man  by  Raum,  Senator,  Luciani,  and  Grawitz,^ 
do  not,  however,  show  that  such  an  increase  is  either  constant  or  in- 
variable in  fasting  men.  Twenty-four  hours'  fasting  usually  suffices 
to  raise  the  red  cells  of  dogs  400,000-500,000,  and  in  captivity  they 
may  emaciate  from  starvation  while  the  red  cells  continue  above  normal 
(Hosslin),  but  in  man  there  has  been  a  lack  of  uniformity  in  the 
changes  observed.  Senator  and  Luciani  finding  an  irregular  increase 
in  the  number  of  red  cells  in  the  professional  fasters  Cetti  and  Lucci, 
while  Raum  and  Grawitz  ^  found  a  distinctly  anemic  condition  es- 
tablished in  healthy  fasting  men. 

3.  Sex. — The  relative  anemia  of  women  is  not  found  until  men- 
struation is  established  at  about  the  fourteenth  to  sixteenth  years. 
Indeed,  Stierlin,  who  examined  the  blood  of  ten  boys  and  ten  girls 
under  15  years,  found  a  slight  and  rather  uniform  difference  in  both 
red  cells  (350,000)  and  Hb  (2.5  percent)  in  favor  of  female  children. 

While  the  figures  of  Welcker,  500,000,  have  been  generally  accepted 
as  representing  the  difference  between  the  blood  of  men  and  that  of 
women,  Leichtenstern,  from  191  observations,  placed  this  difference  at 
about  one  million  cells.  Later  reports  (Ziegler,  Stierlin),  as  well  as 
common  clinical  experience,  would  seem  to  indicate  that  the  difference 
does  not  usually  amount  to  500,000,  and  that  when  the  number  falls 
below  4,500,000  in  women  there  is  some  distinctly  pathological  con- 
dition to  account  for  the  relative  anemia.  There  are  at  hand  no 
systematic  comparisons  of  the  number  of  red  cells  in  women  at  differ- 
ent ages,  apart  from  the  immediate  effects  of  menstruation  and  preg- 
nancy. Stierlin  has  shown  that  both  red  cells  and  Hb  are  subject  to 
more  extensive  physiological  variations  in  women  than  in  men.  In 
specific  gravity  Dieballa  found  that  with  the  same  red  cells  and  Hb 
the  blood  of  women  averages  .0025  less  than  that  of  men. 

Mexstruatiox. — Since  a  hemorrhage  which  removes  less  than  one- 
fiftieth  to  one-twentieth  of  the  total  volume  of  blood  fails  to  noticeably 
affect  the  blood  (Vierordt),  the  menstrual  flow,  normally  about  100- 
200  cc.  and  extending  over  a  period  of  some  days,  usually  fails  to  re- 
duce the  red  cells.  On  the  contrary  both  red  cells  and  Hb  have 
frequently  been  found  slightly  increased  after  normal  menstruation. 
(Vierordt,  Hayem,   Duperie,  Scherpf,  Reinl,  Reinert.)      This   result 


PLETHORA.     POLYCYTHEMIA.  91 

has  been  referred  to  stimulation  of  blood-forming  organs.  A  slight 
leucocytosis  has  also  been  noted  by  Hayem,  Moleschott,  and  Re  inert. 
The  clinical  rule  that  normal  menstruation  in  health}'  subjects  fails  to 
induce  anemia  but  may  do  so  when  associated  with  other  causes 
of  anemia,  is  borne  out  by  Reinert's  observations  on  a  chlorotic 
girl.  In  this  patient  a  moderate  flow  reestablished  through  the  use 
of  iron  failed  to  lower  the  blood  count,  but  at  two  succeeding  periods 
more  profuse  discharge  was  followed  by  a  reduction  in  7  days  of 
700,000  cells.  The  changes  which  occur  under  the  most  favorable 
circumstances  are  probably  illustrated  by  the  results  of  Sfameni,  who 
examined  the  blood  of  six  healthy  women  before,  during,  and  after 
menstruation.  He  found  that  normal  menstruation  reduces  the  Hb 
4—15  percent  and  the  red  cells  220,543.  During  the  menstrual 
period  the  leucocytes  are  usually  slightly  increased,  average  330,  and 
the  decrease  of  red  cells  is  less  marked  (122,443).  In  the  inter- 
menstrual period  the  red  cells  slowly  increase,  reaching  a  maximum 
three  days  before  the  succeeding  floAV. 

In  spite  of  the  above  largely  negative  results,  it  can  hardly  be 
doubted  that  a  slightly  disordered  menstruation  is  a  most  important 
factor  in  the  etiology  of  chlorosis. 

Pregxaxcy. — After  passing  through  many  phases  of  conjecture, 
opinions  regarding  the  condition  of  the  blood  in  pregnancy  are  now 
based  on  numerous  observations  extended  and  summarized  by  Schroeder, 
which  show  that  pregnancy  in  itself  has  little  influence  on  the  Hb  or 
red  cells  of  the  blood,  and  that  if  anemia  exists  it  is  to  be  referred 
to  unhygienic  conditions.  Post-partum  anemia  should  not  continue 
longer  than  10—14  days,  and  may  be  succeeded  by  a  slight  increase  of 
red  cells  above  the  normal. 

PLETHORA.      POLYCYTHEMIA. 

Although  the  subject  of  plethora  belongs  properly  to  the  physiologist 
or  general  pathologist,  the  clinical  importance  of  the  condition  requires 
for  it  some  notice  in  a  work  of  the  present  character.  It  has  already 
been  shown  that  there  are  good  grounds  for  accepting  the  old  belief 
that  there  are  considerable  physiological  and  pathological  variations  in 
the  total  quantity  of  blood  in  the  body,  and  it  remains  to  consider  here 
those  factors  which  directly  affect  the  proportion  of  red  cells. 

Pohjcythemia  may  arise  either  from  an  increase  in  the  number  of 
red  cells  or  from  a  decrease  in  the  volume  of  the  plasma.  Practically 
it  can  hardly  be  said  that  a  true  polycythemia  from  the  first-named 
cause  is  ever  observed,  as  the  blood-forming  organs  are  never  known 
to  produce  an  excess  of  red  cells,  and  the  effects  of  transfusion  of  blood 
are  very  transitory.  Polycythemia  from  decrease  in  the  volume  of 
plasma,  however,  is  very  frequently  encountered,  and  among  its  causes 
may  be  mentioned  diarrhea,  dysentery,  cholera  (Schmidt,  Hayem)  or  any 
disease  attended  with  excessive  watery  exudate  ;  conditions  marked  by 
insufficient  aeration  of  the   blood  and  venous  stasis,   as  endocarditis, 


92       MORPHOLOGY  AND  PHYSIOLOGY  OF  THE  BED   CELLS. 

emphysema,  asphyxia,  and  in  the  peculiar  permanent  polycythemia, 
observed  at  high  altitudes  ;  the  administration  in  therapeutic  or  poison- 
ous doses  of  various  drugs,  lyraphagogues  (Grawitz*),  phosphorus  (v. 
Jaksch),  pilocarpine,  eserine,  etc.  (Hamburger),  and  cold  baths.  Various 
other  influences  leading  to  local  polycythemia  have  been  mentioned  in 
the  Introductory  Section. 

The  danger  of  overlooking  the  true  cause  of  polycythemia  is  well 
illustrated  in  Timofjewsky's  experiments,  when  after  the  intra-venous 
injection  of  pus  an  increase  of  red  cells  of  1.5-2  million  w^as  found  to 
result  from  concealed  exudates  from  mucous  and  serous  membranes. 

The  Polycythemia  of  the  New-Born. — The  marked  relative  poly- 
cythemia of  the  blood  of  new-born  infants  has  been  constantly  attested. 
The  following  averages  have  been  observed  : 

Hayem 5,368,000 

Sorensen 5,665,000 

Otto 6,165,000 

Helot 5,531,000 

Schiff 5.825,000 

Bidone 6,500,000 

While  the  averages  of  considerable  numbers  of  cases  reported  by 
the  above  authors  are  rather  uniform,  very  marked  variations  have 
been  noted,  referable  to  changes  at  different  periods  of  the  day,  and  to 
individual  peculiarities.  Hayem  and  Helot  found  that  too  early  liga- 
ture of  the  cord  might  cause  a  reduction  of  one-half  to  one  million  cells. 
During  the  first  weeks  the  polycythemia,  which  is  usually  highest  be- 
fore the  first  nursing,  gradually  disappears  at  the  rate  of  about  250,000 
cells  weekly,  but  while  the  average  fall  of  a  considerable  number  of 
cases  is  very  regular,  there  are  marked  daily  variations  in  individuals 
of  from  one-half  to  one  million.  (Schiff.)  No  definite  relation  between 
the  changes  in  body  weight  and  the  number  of  red  cells  has  been 
traced,  but  a  marked  reduction  usually  follows  each  nursing. 

The  cause  of  the  polycythemia  of  the  new-born  is  doubtless  to  be 
found  in  a  temporary  concentration  of  the  blood  in  which  a  number  of 
factors  are  concerned.  The  loss  of  water  during  the  first  hours  of 
respiration  has  been  regarded  as  an  important  influence  (Preyer),  but 
can  hardly  account  for  the  condition  of  the  blood  in  the  first  hours 
after  birth.  The  writer  finds  that  the  polycythemia  bears  a  rather 
close  relation  to  the  degree  of  cyanosis  exhibited  by  the  expressed 
blood-drop,  and  believes  that  the  concentration  of  blood  is  principally 
referable  to  a  state  of  relative  stasis  which  is  then  established  in  the 
peripheral  capillaries. 

The  Polycythemia  of  High  Altitudes.— The  observations  of  Bert 
in  1882  that  the  blood  of  animals  from  the  Bolivian  plateaus  showed 
much  increased  capacity  to  absorb  oxygen  led  Viault  to  examine  his 
own  blood  while  sojourning  in  the  Andes  and  to  find  that  at  an  eleva- 
tion of  4,392  meters  the  red  cells  had  increased  from  five  to  eight  mil- 
lions, many  of  them  being  undersized.  In  the  blood  of  animals  he 
found  a  similar  polycythemia  but  no  increase  in  oxygen. 


THE  POLYCYTHEMIA    OF  DIARRHEAL  DISEASES.  93 

These  observations  were  vei'ified  by  Egger,  Koppe,  Wolif,  and  many 
others,  who  found  that  the  increase  begins  almost  immediately  upon 
the  change  in  altitude,  amounting  at  times  to  one  million  cells  in  24 
hours,  reaching  its  limit  in  about  two  weeks,  after  which  the  numbers 
remain  permanently  high.  On  returning  to  sea  level  the  polycythe- 
mia promptly  disappears,  even  more  rapidly  than  it  is  established. 
(Mercier.)  The  percentage  of  Hb  appears  to  be  less  affected,  and  the 
volume  of  red  cells  not  at  all.  Egger  found  no  change  in  the  dry  residue 
of  the  blood  of  two  rabbits,  but  Grawitz  found  the  residue  distinctly 
increased  in  a  rabbit  which  had  been  confined  in  a  rarefied  atmosphere. 
The  blood  of  anemic  and  phthisical  patients  is  less  markedly  and  per- 
manently affected  than  that  of  healthy  individuals. 

The  significance  of  these  changes  has  not  been  fully  explained,  but 
it  seems  most  probable  that  the  polycythemia,  if  it  really  exists  at  all, 
is  an  effect  of  concentration  of  the  blood,  brought  about  by  Nature's 
effort  to  adjust  the  respiratory  function  to  the  smaller  proportion  of 
oxygen  in  the  rarefied  atmosphere.  That  the  state  of  the  blood  is  one 
of  simple  concentration  is,  however,  rendered  uncertain  by  the  low 
percentage  volume  of  red  cells.  Egger  and  Koppe  maintain  that  there 
is  a  formation  of  new  red  cells,  but  the  microcytes  found  cannot  figure 
as  such  evidence.  Normoblasts  ought  to  be  present  if,  as  Grawitz 
says,'  about  one  liter  of  new  blood  has  been  produced  in  24  hours, 
while  the  polycythemia  promptly  subsides  at  the  sea  level  without 
yielding  signs  of  blood  destruction.  The  possibility  that  the  cells  are 
concentrated  in  the  capillaries  is  negatived,  since  Egger  found  a  simi- 
lar increase  in  the  large  internal  arteries  of  rabbits,  while  the  sugges- 
tion of  Fick  that  the  red  cells  may  enjoy  a  lengthened  existence  in 
the  circulation  does  not  commend  itself. 

Several  observations,  recently  reviewed  by  Starcke,  indicate  that 
the  results  obtained  by  the  hematocytometer  are  markedly  dependent 
upon  temperature  and  barometric  pressure,  and  suggest  that  many,  if 
not  all,  of  the  peculiarities  of  the  blood  at  high  altitudes  may  possibly 
be  referable  to  this  cause. 

Residence  at  the  sea  coast  is  frequently  followed  by  increase  in  the 
number  of  red  cells  as  a  part  of  improvement  in  general  health. 

In  the  tropics  most  Europeans  become  more  or  less  anemic  until 
fully  inured  to  the  various  unhygienic  influences  obtaining  there. 

The  Polycythemia  of  Diarrheal  Diseases. — The  concentration  of 
the  blood  which  results  from  depletion  of  fluids  through  the  intestine 
is  seen  to  a  slight  extent  in  severe  simple  diarrhea,  more  distinctly  in 
acute  dysentery  and  at  its  height  in  cholera. 

An  increase  of  two  millions  in  the  number  of  red  cells  has  been  ob- 
served by  Hay  within  two  hours  after  the  administration  of  21  grm.  of 
Glauber's  salts  in  concentrated  solution,  and  Brouardel  demonstrated 
less  clearly  a  marked  increase  after  purgation  by  croton  oil  and  jalap. 
When  given  in  dilute  solution  the  effects  of  the  salines  are  of  course  less 
evident.  Clinically,  a  moderate  polycythemia  has  been  observed  after 
severe  diarrhea  or  vomltinoj,  but  the  effects  are  usuallv  transient. 


94       MORPHOLOGY  AND  PHYSIOLOGY  OF  THE  RED   CELLS. 

In  dysentery,  polycythemia  may  be  expected  only  when  the  diarrhea 
is  acute  and  the  quantity  of  blood  lost  is  slight.  Usually  an  anemia  is 
established  by  direct  loss  of  blood. 

In  typhoid  fever  the  progress  of  the  anemia  is  often  greatly  ob- 
scured by  the  concentration  of  blood  in  cases  marked  by  severe  diar- 
rhea. In  cholera  the  conditions  are  specially  favorable  for  watery 
depletion  of  the  blood  and  tissues  and  remarkably  high  counts  have 
been  recorded  in  the  late  stages  of  this  disease. 

Polycythemia  of  Endocarditis,  Venous  Stasis,  etc. — Very  numer- 
ous observations  have  shown  that  at  some  stages  of  endocarditis  a 
marked  polycythemia  is  established,  and  largely  through  the  studies  of 
Oertel  and  of  Grawitz  it  has  been  shown  that  this  concentration  is 
found  in  conditions  marked  by  chronic  stasis,  cyanosis,  edema,  and  is 
more  marked  in  the  capillaries  than  in  the  veins  or  arteries.  The 
same  condition  is  seen  in  chronic  stasis  from  other  causes.  (Peiper, 
Grawitz.'^) 

Phosphorus  Poisoning. — In  cases  of  phosphorus  poisoning  of  mod- 
erate intensity,  but  fatal,  Taussig  observed  an  increase  in  red  cells  to 
8.5  millions,  v.  Jaksch  an  increase  from  4.3  to  8.25  millions,  and  Lim- 
beck an  increase  to  nearly  8  millions.  The  fact  that  the  polycythemia 
does  not  appear  until  the  toxic  symptoms  are  marked  and  usually 
subsides  with  them  about  the  fourth  or  fifth  day,  indicates  that  it  re- 
sults largely  from  depletion  of  the  blood  through  the  vomitus.  Von 
Jaksch  found  no  simultaneous  increase  in  the  proportion  of  albumens. 
The  leucocytes  are  usually  diminished,  sometimes  slightly  increased, 
and  the  Hb-index  is  lowered. 

Illuminating  Gas  Poisoning. — Munzer  and  Palma  and  Limbeck 
have  observed  moderate  polycythemia  in  three  cases  (5.7,  6.63,  5.7 
millions),  with  slight  leucocytosis,  13,300  in  one  case.  The  condition 
must  be  referred  to  venous  stasis. 

Polycythemia  After  Cold  Baths. — An  increase  of  red  cells  of  .5  to 
1.5  millions  has  been  observed  by  many  writers  to  occur  after  the 
application  of  cold  baths.  (Toenissen,  Winternitz,  Knopfelmacher, 
Thayer.)  The  change  is  observed  immediately  after  the  bath  and  con- 
tinues after  cyanosis  has  disappeared  and  while  the  patient  is  shiver- 
ing, but  soon  disappears  thereafter.  It  is  often  missing  after  15-20 
minutes.  The  leucocytes  also  are  usually  increased  (15,000-20,000). 
The  condition  is  ])robably  referable  to  concentration  of  the  blood  due 
to  stimulation  of  the  vaso-constrictors,  and  is  probably  more  marked, 
if  not  exclusively  present,  in  the  peripheral  capillaries.  Yet  some 
have  suggested  that  a  new  formation  of  cells  may  be  indicated  by  the 
change.     It  may  be  noted  here  that  warm  baths  have  a  contrary  effect. 

Influence  of  Therapeutic  Measures  on  the  Red  Cells. 

Iron. — The  remarkable  effect  of  this  agent  upon  the  blood  in  suitable 
cases  of  anemia  is  seen  in  a  rapid  increase  in  the  number  of  red  cells 
and  in  a  later  but  rather  more  uniform  increase  of  Hb.     According  to 


INFLUENCE  OF  THERAPEUTIC  MEASURES  ON  RED  CELLS.       95 

Hayem  the  effects  of  iron  in  chlorosis  may  be  divided  into  two  periods, 
in  the  first  of  which  the  increase  in  red  cells  outstrips  that  in  Hb  until 
a  normal  number  is  reached,  while  in  the  second  period  the  Hbof  the 
new  red  cells  is  gradually  brought  to  the  normal.  The  appearance  in 
such  cases  of  many  small  red  cells  deficient  in  Hb  has  been  commonly 
noted,  but  Stifler  finds  they  are  not  equally  abundant  at  all  periods  of 
the  regeneration  of  the  blood,  that  the  increase  of  cells  occurs  period- 
ically, and  that  at  the  height  of  the  periods  many  pale  cells  are  found 
which  increase  in  Hb-coutent  while  the  numbers  of  cells  remain  nearly 
constant. 

Again,  Willcox  finds  a  difference  in  the  effects  of  small  and  of  large 
doses  of  iron.  When  small  doses  are  used  the  red  cells  outstrip  the 
Hb  but  with  large  doses  both  increase  in  equal  proportion.  Laache 
also  has  observed  equal  progress  in  cells  and  Hb  in  cases  of  chlorosis. 
It  would  seem  therefore  that  the  regeneration  of  the  blood  under  iron 
may  follow  any  one  of  the  above  three  courses,  depending  upon  various 
circumstances  which  cannot  here  be  further  discussed. 

Hayem  and  Reinert  have  called  attention  to  the  tendency  of  the  red 
cells  to  diminish  slightly  after  reaching  a  normal  number,  until  the 
restoration  of  Hb  becomes  complete.  Of  the  two  Reinert  believes 
that  the  progress  of  the  Hb  is  the  more  uniform.  Limbeck  finds  that 
the  red  cells  usually  diminish  for  some  days  when  the  administration 
of  iron  is  begun. 

Indications  for  the  Use  of  Iron. — The  specific  effects  of  this 
drug  being  centered  primarily  on  the  Hb,  the  chief  indication  for  its 
use  and  the  best  results  are  obtained  in  cases  of  pure  chlorosis  with 
marked  loss  of  Hb  and  moderate  reduction  in  cells.  In  secondary 
anemia  its  curative  action  is  less  certain.  Witli  the  appearance  of 
larger  cells  icith  normal  or  increased  Hb,  the  use  of  iron  becomes  much 
less  effective,  and  when  the  Hb-index  is  above  normal  it  seems  to  be 
entirely  valueless. 

A  large  part  of  the  effects  attributed  to  iron  may  be  obtained  solely 
by  the  improved  hygienic  and  dietetic  conditions  which  are  usually  en- 
joyed during  its  administration.  The  influence  of  rest  in  bed,  selected 
diet,  baths,  oxygen,  massage,  etc.,  has  long  been  recognized  as  a  very 
powerful  adjunct  in  the  treatment  of  anemia.  But  numerous  observa- 
tions go  to  show  that  while  the  numbers  of  cells  may  be  greatly  in- 
creased by  these  means  yet  the  complete  restoration  of  Hb  in  severe 
chlorosis  is  seldom  as  complete  or  rapid  as  when  iron  is  freely  given, 
so  that  a  specific  influence  of  this  drug  must  be  admitted. 

Of  the  great  variety  of  preparations  employed  at  various  times,  prob- 
ably the  more  irritant  preparations  in  large  doses  are  still  acknowledged 
to  yield  the  best  results  when  well  borne  by  the  stomach. 

The  curative  action  of  iron  in  anemia  is  still  lai-gely  unexplained,  but  the 
theory  of  Binz  appears  to  remain  the  most  rational.  Binz  holds  that  in 
chlorosis,  as  a  result  of  prolonged  malnutrition,  the  absorption  of  iron  from 
the  food  becomes  deficient  while  its  excretion  through  the  liver  and  bile  re- 
mains undiminished,  and  the  blood  becomes  impoverished  in  this  principle. 


96       MORPHOLOGY  AND  PHYSIOLOGY  OF  THE  RED  CELLS. 

By  administering  iron  in  large  doses  it  is  more  readily  absorbed  and  the  de- 
ficiency is  overcome. 

Buno-e's  theory,  based  on  Sir  Andrew  Clark's  belief  that  chlorosis  is  an 
autointoxication  of  intestinal  origin,  assumes  that  the  iron  administered  is 
not  absorbed  in  increased  quantity  but  exerts  its  curative  influence  by  neu- 
tralizing toxic  agents  in  the  intestine.  These  assumptions  have  been  largely 
disproved  by  v.  Noorden,  Rethers  and  Morner,  who  have  demonstrated  that 
abnormal  putrefactive  processes  in  the  intestine  are  not  usually  present  in 
chlorosis,  and  by  the  demonstration  that  increased  ingestion  of  inorganic 
iron  is  followed  by  its  increased  absorption  principally  or  exclusively  in  the 
duodenum.  (Kuiikel,  Woltering,  Hall,  McCallum,  Hochaus  and  Quincke, 
Cloetta  Hoffman.)  v.  Noorden's^  conclusions  seem  to  embody  the  results 
thus  far  obtained,  that  while  iron  in  the  nucleo-proteid  combinations  of  the 
food  is  constantly  available  in  chlorosis,  it  is  either  not  absorbed  or  is  not 
appropriated  by  the  blood,  whereas  when  given  in  large  doses  it  is  absorbed 
in  excess  and  exerts  a  specific  influence  upon  the  bone  marrow.  The  prob- 
lem of  the  nature  of  this  influence  remains  of  course  untouched. 

Arsenic. — While  iron  is  contraindicated  by  the  appearance  in  the 
blood  of  megalocytes  with  increased  Hb,  under  these  circumstances 
arsenic  frequently  exerts  an  almost  specific  eifect  in  increasing  the 
number  of  red  cells  and  in  stimulating  the  production  and  more 
uniform  distribution  of  Hb.  Its  field  is  therefore  chiefly  in  the 
severe  and  chronic  anemias,  but  in  the  simpler  forms  the  action  of 
iron  is  often  accelerated  by  combination  with  arsenic.  Its  therapeutic 
effects  in  disease  are  rendered  more  obscure  by  the  fact  that  in  health 
it  causes  diminution  in  the  number  of  red  cells.  (Stierlin,  Delpeuch.) 
Stockman  and  Greig  claim  to  have  found  evidences  of  increased  for- 
mation of  red  cells  in  the  marrow  of  rabbits  after  long  use  of  arsenic, 
yet  the  number  of  red  cells  in  the  blood  remained  normal. 

Mercury. — Numerous  observations  upon  the  effects  of  mercury  in 
syphilis  dating  from  those  of  Wilbouchewitch,  and  Keyes,  in  1874-6, 
to  those  of  Lezius,  and  Martin  and  Hiller,  in  1890,  have  failed  to 
demonstrate  that  this  drug,  in  therapeutic  doses,  has  any  direct  effect 
upon  the  red  cells.  It  has  been  shown,  however,  that  in  doses  beyond 
a  limit  which  varies  with  individuals  and  circumstances,  mercury  usu- 
ally causes  a  prompt  reduction  in  both  cells  and  Hb,  and  distinct 
anemia.  It  does  not  appear,  from  these  studies,  that  the  improved 
condition  observed  in  the  blood  of  syphilitics  using  mercury  is  separ- 
able from  the  removal  of  the  virus  and  the  consequent  general  im- 
provement in  health.  A  reduction  in  Hb  and  cells  has  been  frequently 
observed  soon  after  beginning  mercurial  treatment  or  after  the  drug 
has  been  pushed  and  seems  to  continue  until  the  sy.stem  becomes  in- 
ured or  the  dose  has  been  reduced  to  a  proper  limit,  so  that  the  ex- 
amination of  the  blood,  as  shown  by  Martin  and  Hiller,  may  be  made 
a  valuable  guide  in  the  administration  of  this  remedy.  Most  of  the 
conflicting  results  reported  may  be  explained  on  the  grounds  that  in 
doses  beyond  a  variable  limit,  especially  at  the  beginning  of  treatment, 
mercury  reduces  the  cells  and  Hb  ;  that  when  the  original  disease  is 
being  successfully  combated  the  anemia  usually  improves  ;  and  that 
apart  from  its  antisyphilitic  powers  the  drug  has  little  effect  upon  the 
blood.     (Cf.  section  on  Syphilis.) 


OLIGOCYTHEMIA.  97 

Lead. — In  cases  of  chronic  lead  poisoning  the  blood  commonly  shows 
a  moderate  grade  of  secondary  chlorotic  anemia.  Zinn  records  an 
acute  case  with  hemorrhages  in  which  the  red  cells  numbered  4  mil- 
lions, leucocytes  3,300,  Hb  58  percent,  s.  g.  1.048.  More  severe  cases 
have  been  reported  Avith  anemia  usually  in  proportion  to  length  of  the 
disorder  by  Malassez,  2.2  million  red  cells;  by  Limbeck,  2.2  millions  ; 
and  by  Brochin,  1.3  millions.  Hayem  states  that  the  anemia  of  chronic 
plumbism  is  characterized  by  its  close  resemblance  to  chlorosis,  by  the 
rapid  decrease  in  cells  while  the  patient  suffers  from  colic,  and  by  the 
absence  of  leucocytosis.  Hayem  saw  no  case  with  increased  Hb-index 
but  Malassez  reported  megalocytes  and  megaloblasts  as  abundantly 
present  in  some  cases. 

This  anemia  is  commonly  attributed  to  gastro-intestinal  disturb- 
ance, but  Hayem  referred  it  to  destruction  of  cells  from  direct  action 
of  lead. 

Maragliano  demonstrated  increased  globulicidal  activity  of  the  serum 
in  chronic  plumbism  and  Grawitz  has  noted  considerable  degrees  of 
granular  degeneration  of  the  red  cells. 

OLIGOCYTHEMIA. 

Hemorrhage  causes  a  peculiar  type  of  impoverishment  of  the  blood  in 
which  the  oligocythemia  is  associated  with  other  important  changes 
in  the  plasma.  The  progress  of  events  in  the  circulation  which  follow 
a  severe  loss  of  blood  involves  the  consideration  of  many  physiological 
processes.  One  of  the  first  effects  is  a  lowering  of  blood  pressure, 
which  is  followed  by  an  increased  flow  of  lymph  and  by  a  rapid  trans- 
fusion of  fluids  from  the  tissues  through  the  capillary  walls.  The  fluid 
which  replaces  the  lost  blood  is  necessarily  of  different  composition 
from  the  plasma  and  its  addition  to  the  circulation  markedly  affects 
the  composition  of  the  blood  after  hemorrhage.  The  lymph,  being  rich 
in  salts  and  poor  in  albumens,  and  water  from  the  tissues  passing 
through  capillary  walls  more  readily  than  albumens,  the  blood  when 
restored  to  its  normal  volume  is  found  to  be  low  in  albumens,  rich  in 
salts,  and  poor  in  red  cells.  After  rapid  hemorrhages  the  alkalinity  of 
the  blood  falls  (Zuntz),  and  its  content  in  sugar  increases  (Bernard, 
Mering),  this  principle  being  derived  from  the  glycogen  of  the  liver 
(Schenk),  while  the  coagulability  is  much  increased.  The  hydremia 
affects  principally  the  plasma,  but  Herz  found  the  relative  volume  of 
the  red  cells  tripled  ten  hours  after  a  very  severe  hemorrhage,  indi- 
cating that  they  had  absorbed  much  water. 

In  small  animals  (rabbits)  the  restoration  of  the  voliuiie  of  blood 
takes  place  very  rapidly  and  oligocythemia  is  observed  almost  immedi- 
ately after  the  hemorrhage,  but  in  larger  animals  (dog,  man)  a  distinct 
interval  is  required  before  the  fluids  have  replaced  the  lost  blood,  and, 
according  to  Limbeck,  35—40  minutes  may  elapse  before  a  distinct  re- 
duction in  red  cells  is  observed  after  moderately  severe  hemorrhages. 

The  changes  in  the  number  of  red  cells  following  hemorrhages  are 
7 


98       MORPHOLOGY  AND  PHYSIOLOGY  OF  THE  RED   CELLS. 

somewhat  irregular,  but  from  the  observations  of  Huherfauth,  Lyon, 
Otto,  Koeppe,^  Viola  and  Jona,  it  has  been  shown  that  in  dogs  and  man 
a  single  large  hemorrhage  reduces  the  red  cells  in  proportion  consider- 
ably less  than  the  effect  upon  the  volume  of  blood,  beginning  about 
one-half  hour  after  the  operation,  reaching  a  maximum  effect  in  3-4 
days,  and  followed  by  a  restoration  to  the  normal  number  in  19-34 
days.     (Lyon.) 

In  small  animals  (rabbits)  the  rate  of  decrease  is  more  rapid,  the 
lowest  point  being  reached  in  a  few  hours,  and  recovery  also  following 
earlier.  With  slow  hemorrhages  of  large  extent  (3-4  percent)  the 
minimum  is  reached  in  1-9  days,  depending  largely  upon  the  size  of 
the  animal,  and  recovery  is  complete  in  14-22  days.  (Huhnerfauth.) 
After  lesser  hemorrhages  (1-3  percent)  full  recovery  follows  in  5-14 
days,  while  small  losses  leave  no  trace  after  2-5  days.  (Lyon.)  These 
periods  depend  much  upon  the  state  of  nutrition,  and  it  has  been  found 
that  full  diet,  free  supply  of  water,  and  transfusion  of  salines,  greatly 
accelerate  recovery.  Ehrlich  believes  that  the  continuous  reduction  in 
cells  is  partly  referable  to  the  solution  of  many  of  them  as  the  plasma 
becomes  more  watery. 

During  both  phases,  the  Hb  falls  behind  the  changes  in  the  cells 
(Otto,  Reinert),  owing  to  the  formation  of  numerous  microcytes  by  the 
splitting  of  red  cells.  (Koeppe.)  Grawitz  however  does  not  believe 
that  such  splitting  of  red  cells  can  occur.  Nucleated  red  cells  of  nor- 
mal or  very  small  size  appear  within  a  few  hours  and  in  large  numbers 
after  severe  hemorrhage,  and  even  after  small  losses,  if  sudden.  That 
they  are  drawn  into  the  circulation  mechanically  is  indicated  by  their 
usual  absence  after  slow  bleediugs  of  much  larger  extent.      (Zenoni.^) 

Changes  in  the  size  and  shape  of  the  cells  are  conmionly  observed 
especially  after  large  bleedings.  Microcytes  and  slightly  enlarged 
megalocytes  usually  appear  in  2-4  days,  at  the  period  of  greatest  oligo- 
cythemia. (Koeppe.)  The  extent  and  duration  of  these  changes  de- 
pend largely  on  the  grade  of  anemia  established.  Polychromatophilia 
is  usually  marked  within  24  hours. 

Healthy  men  recover  rapidly  from  moderately  severe  hemorrhages 
and  so  completely  that  the  red  cells  may  be  more  numerous  than  be- 
fore, from  apparent  over-stimulation  of  the  marrow.  (Otto,  Hall  and 
Eubank.)  Small  and  repeated  hemorrhages,  on  the  other  hand,  have 
led  to  some  of  the  most  severe  forms  of  anemia  ever  recorded,  in  which 
the  morphological  changes  of  pernicious  anemia  are  pronounced,  but 
the  prevailing  feature  of  the  blood  is  the  loss  of  Hb. 

The  leucocytes  are  usually,  but  not  always,  much  increased  (20,000— 
40,000),  the  neutrophile  cells  being  most  affected,  the  eosinophils 
sometimes  appearing  in  considerable  numbers  (Lyon,  Hall  and 
Eubank),  and  the  small  lymphocytes  showing  a  relative  increase. 
(Rieder.)  Ehrlich  and  Lazarus  found  13.7  percent  of  myelocytes  in  a 
marked  post-hemorrhagic  leucocytosis,  and  in  one  of  the  writer's  cases 
of  splenectomy  with  profuse  hemorrhage  the  blood  for  some  days 
closely  resembled  that  of  myelogenous  leukemia. 


OLIG  OCYTHEMIA. 


99 


The  post-hemorrhagic  leucocytosis  is  referred  by  Virchow  to  the  re- 
tention of  cohesive  leucocytes  in  the  small  vessels,  by  Ehrlich  to  their 
active  new  production  in  bone  marrow,  and  by  Rieder  to  the  outpour  of 
the  lymph.  It  is  usually  persistent  in  some  degree  till  the  regenera- 
tion of  the  blood  is  nearly  complete. 

From  very  extensive  observations  in  Mickulicz'  clinic,  Bierfreund 
found  that  the  regeneration  of  the  blood  is  most  rapid  in  male  sub- 
jects between  20-40  years  of  age,  is  considerably  earlier  in  males  than 
in  females,  and  in  adults  than  in  children  or  old  persons.  A  loss  of 
5  percent  Hb  was  found  to  lengthen  the  period  of  regeneration  2—8 
days.  The  minimum  percentage  of  Hb  was  reached,  after  a  loss  of  10-1 5 
percent,  in  3.5  days;  after  16-20  percent,  in  5.8  days;  after  21-25 
percent,  in  6.5  days  ;  after  26  percent,  in  9.6  days,  and  in  women 
usually  one  day  later  than  with  men. 

It  is  significant  that  in  Bierfreund's  tables  there  are  no  averages  on 
patients  losing  more  than  30  percent  of  Hb,  indicating  that  when  a 
surgical  operation  causes  a  loss  of  30  percent  Hb  it  is  usually  fatal. 
Mickulicz  attempted  to  deduce  from  this  fact  the  rule  that  no  opera- 
tion should  be  undertaken  unless  the  patient  could  stand  such  a  loss, 
but  it  is  difficult  to  see  any  great  practical  application  of  such  a  rule. 

Bierfreund's  Table,  Showing  Average  Time  of  Full  Regeneration 
OF  Blood  After  Hemorrhage. 


Loss  of  Blood 

Sex. 

Age(yrs.). 

m>f. 

M. 

F. 

1-10 

10-20 

20-30 

30-40 

40-50 

50-60 

60+ 

10-15 

12  7 
17  9 
20"  3 

27 

17.1  days. 
23.5 
23.5 
31.3 

20 
21 
22.5 

13.2 
19.0 
21.3 

10.8 
12.5 
17.6 

10.4 
16.2 

16 
21 
19 

17. 
22.7 

28.0 

16-20 
21-25 

23.8 
27. 

26 

Anemia  Following  Repeated  Small  Hemorrhages. — While  very  marked 
changes  in  the  blood  following  a  single  large  hemorrhage  may  be  rather 
promptly  restored,  the  regeneration  is  very  greatly  retarded  after  even 
one  repetition  of  the  hemorrhage,  and  when  they  are  frequently  re- 
peated, there  is  soon  established  a  severe  form  of  chronic  anemia.  It 
does  not  appear  that  this  anemia  differs  greatly  from  other  equally  se- 
vere secondary  forms,  but  it  is  usually  characterized  by  marked  reduc- 
tion in  the  albumen  (less  of  the  globulin)  of  the  plasma  and  serum  ;  by 
lowering  of  the  dry  residue  and  ash,  due  to  loss  of  Fe,  P  and  K,  which 
more  than  balances  the  increased  Na  ;  and  by  lowered  alkalinity. 
Besides  the  actual  withdrawal  of  albumen,  repeated  hemorrhages  seem 
to  have  almost  a  specific  effect  in  increasing  fat  formation  at  the  ex- 
pense of  albumen  both  of  the  blood  and  tissues.     (Leube.) 

The  loss  of  red  cells  is  here  an  accurate  measure  of  the  grade  of 
anemia  and  all  ordinary  forms  of  their  degeneration  are  observed.  In 
mild  cases  the  loss  of  Hb  is  relatively  slight  but  in  some  severe  cases 
the  Hb-percentage  and  index  are  very  low.  On  the  other  hand  there 
can  be  no  doubt  that  the  state  of  the  blood  following  repeated  small  hem- 


100     MORPHOLOGY  AND  PHYSIOLOGY  OF  THE  RED   CELLS. 

orrhages  cannot  always  be  distinguished  from  that  of  primary  pernicious 
anemia  with  increased  Hb-index.  Anemia  from  hemorrhages  is  one 
of  the  secondary  forms  most  commonly  marked  by  leucocytosis,  yet 
this  feature  is  often  not  marked  and  is  not  infrequently  absent. 

With  man  and  animals  the  clinical  effects  of  hemorrhage  vary 
greatly  among  individuals.  Bechampand  Huhnerfauth  find  that  dogs 
withstand  the  loss  of  3-4  percent  of  the  body  weight,  30-40  percent 
of  the  total  volume  of  blood,  if  the  loss  is  gradual,  but  may  perish  after 
smaller  but  more  rapid  bleedings.  As  a  rule  the  smaller  the  animal 
and  the  more  rapid  the  hemorrhage,  the  more  severe  are  its  eifects. 
Adult  male  subjects  usually  die  if  losing  rapidly  50  percent  of  the 
blood,  but  may  survive  much  greater  losses  from  slow  bleeding. 
Children  are  much  more  susceptible  and  may  die  after  very  small 
hemorrhages,  if  rapid,  while  women  withstand  effects  of  hemorrhage 
much  better  than  children  or  men.  The  regeneration  of  the  blood 
however  is  more  rapid  i)i  men  than  in  women.      (Bierfreund.) 

The  quantity  of  blood  which  may  be  lost  without  causing  death 
varies  greatly  among  individual  men  and  animals,  as  the  following 
table  will  illustrate : 

Limits  of  Hemorrhage  from  which  Recovery  has  been  Observed. 


Author. 

Animal. 

Percentage  of 
body  weight  lost. 

Percentage  of 

red  cells 

remaining. 

No  of 
red  cells 
remaining. 

Dog. 

ti 

(( 

n 

(( 

(( 

Kabbit. 

Man. 
Woman. 

n 

2  hemorrhages 
in  6  days. 

4.58 
(not 
fatal. ) 

4.33-5.55 
4.3-7.3 
5.48-6.57 
average 

5.12 

5.4           5.44 
(even       (always 
chance. )     fatal. ) 

4.5 

3. 

50 

50 

32% 

11% 

Hayem 

Kireeff  

Maydel 

Schram 

Landerer 

Feis 

■t 

Andral,  Behier. 
Laache 

1,598,000 
1,415,000 

Haveni  

TRANSFUSION  OF    SALT  SOLUTION,   SERUM,  AND 
DEFIBRINATED    BLOOD. 

Siegel  and  Schram  both  found  no  improvement  in  the  regeneration 
of  the  blood  from  the  transfusion  of  salt  solution  or  of  serum  in  ani- 
mals after  bleeding,  and  while  it  has  since  been  shown  that  the  regen- 
eration is  somewhat  more  rapid  and  complete  after  salt  infusion,  yet 
this  procedure  must  be  regarded  as  of  more  value  as  a  means  of  saving 
life  than  as  a  stimulant  to  blood  formation.  The  direct  effects  on  the 
blood  of  infusion  of  defibrinated  blood  seem  to  be  much  more  favorable. 
On  the  other  hand,  after  the  transfusion  of  blood  the  above  ob.servers. 


ORIGIN  OF  SECONDARY  ANEMIA.  101 

and  others,  have  found  a  rapid  increase  in  the  number  of  cells,  and 
Bizzozero  reported  the  same  effect  after  transfusion  of  defibrinated 
blood  in  animals.  Quincke  was  one  of  the  first  to  note  an  increase  in 
red  cells  in  pernicious  anemia  as  a  result  of  transfusion  of  blood,  and 
similar  observations  have  been  made  by  Ziemsen  in  anemia  and 
scurvy.  It  would  seem  from  the  observations  of  Bizzozero  and  of 
Bareggi  that  the  red  cells  are  quite  resistant  to  the  process  of  defibri- 
nation and  injection.  Of  the  immediate  effects  of  salt  infusion  upon 
the  blood  of  the  human  subject  there  are  a  few  reports  at  hand,  which 
indicate  that  it  has  considerable  influence  in  lowering  the  numbers  of 
red  cells  and  increasing  the  leucocytes. 

ORIGIN  OF  SECONDARY  ANEMIA. 

The  anemia  associated  with  acute  and  chronic  diseases  is  a  result  of 
many  factors  of  varying  prominence  in  different  conditions,  and  re- 
quiring consideration  in  detail. 

Diminished  Nutrition. — Since  the  digestive  powers  are  largely  in 
abeyance  in  severe  febrile  states,  the  loss  of  the  usual  supply  of  albu- 
minous principles  must  figure  to  some  degree  in  the  impoverishment 
of  the  blood.  Although  the  complete  withdrawal  of  food  in  healthy 
men  leads  to  a  simple  "  atrophy  of  the  blood,"  with  other  tissues,  marked 
by  diminution  in  bulk,  polycythemia,  etc.,  but  not  to  anemia  (Hei- 
denhain,  Voit),  it  by  no  means  follows  that  similar  results  would  occur 
in  disease,  while  distinctly  anemic  conditions  are  known  to  result  from 
improper  quality  of  food.  (Lichtenstern.)  Grawitz  (p.  69)  has  found 
that  food  deficient  in  albumen  may  cause  a  diminution  in  the  albumen 
of  the  plasma,  which  may  be  demonstrated  within  4—8  days,  is  more 
marked  when  the  subject  is  exercising,  and  later  affects  also  the  num- 
ber of  cells. 

Diminished  Activity  of  Blood-forming  Organs. — Simultaneously  with 
the  loss  of  digestive  powers,  it  can  hardly  be  doubted  that  the  normal 
process  of  red  cell  formation  must  be  interrupted  in  most  infectious  dis- 
eases. This  conclusion  may  be  based  upon  the  known  effects  of  tox- 
emia upon  cellular  processes,  or  the  absence  of  normal  stimulus  from 
absorbed  food  products,  and  upon  anatomical  conditions  demonstrated 
in  the  bone  marrow.  Regarding  the  last  factor  it  may  be  said  that  the 
leucocytosis  of  pneumonia  is  associated  with  proliferation  of  myelo- 
cytes in  the  marrow  at  considerable  expense  of  normoblasts,  and  in 
typhoid  fever  the  normal  relations  in  the  marrow  cords  are  greatly  dis- 
turbed by  congested,  dilated,  or  even  ruptured  sinuses. 

Increased  Consumption  of  Albumens. — The  toxic  destruction  of  albu- 
mens in  fever  has  been  fully  demonstrated  by  Hallervorden  and  Leube,^ 
and  their  products  noted  in  the  increased  excretion  of  urea,  of  urinary 
pigment  (Jaffe),  and  potash  salts  (Salkowski).  While  the  tissue  proteids 
suffer  most  in  this  process  it  is  but  a  step  to  the  source  of  these  prin- 
ciples in  the  blood.  That  the  albumens  of  the  blood  and  tissues  suffer 
in  some  degree  in  afebrile  cachexias  is  indicated  by  the  results  of 
Miiller's  studies  on  metabolism  in  carcinoma. 


102     MORPHOLOGY  AND  PHYSIOLOGY  OF  THE  RED  CELLS. 

Increased  Destruction  of  Red  Cells. — The  increased  globulicidal 
activity  of  the  serum  in  infectious  and  septic  processes  is  undoubtedly 
a  most  potent  agency  in  the  diminution  of  red  cells,  and  has  been 
demonstrated  by  Maragliano  in  carcinoma,  pneumonia,  typhoid  fever, 
erysipelas,  tuberculosis,  and  many  other  conditions.  The  very  rapid 
deo-lobulization  observed  in  malignant  endocarditis  and  septicemia 
leaves  abundant  evidence  of  this  peculiar  process  also  in  the  pigment 
deposits  found  in  the  viscera.  Of  the  sources  of  the  globulicidal  agent 
little  is  known,  but  it  is  certain  that  the  products  of  disordered  tissue 
metabolism  and  bacterial  toxines  are  capable  of  dissolving  red  cells  when 
injected  into  the  circulation.  Fischer  and  Adler  saw  the  red  cells  fall 
from  6  to  1.3  millions  in  7  days  after  injections  of  streptococcus  cul- 
tures into  a  rabbit;  and  Grawitz  could  find  only  ;>00,000  red  cells  in 
a  remarkably  rapid  case  of  streptococcus  septicemia  in  an  adult  woman. 
Bianchi-Mariotti  found  a  marked  loss  of  Hb  in  direct  proportion  to  the 
quantity  of  culture  used,  after  injections  of  cultures  of  B.  tiiphoxm, 
cholera,  anthrax,  etc. 

There  is  abundant  evidence  to  show  that  in  many  conditions  asso- 
ciated with  acute  infection  and  resulting  from  chronic  cachexia  the  red 
cells  are  abnormally  fragile.  Of  such  evidence  may  be  mentioned  the 
occurrence  of  paroxysmal  hemoglobinemia  on  slight  exj)()sure  to  cold, 
and  the  rapid  development  of  anemia  in  many  mercurialized  subjects. 

Loss  of  Blood  by  Hemorrhage  and  Exudation. — Perhaps  the  majority 
of  severe  cases  of  secondary  anemia  result  from  the  complication  of  the 
original  disease  by  single  or  repeated  hemorrhages.  Post-typhoid 
anemia  is  usually  slight  and  sometimes  absent  if  there  have  been  no 
bleedings  from  the  intestines,  and  cancerous  cachexia  is  very  promj^tly 
aggravated  when  ulceration  and  hemorrhage  supervene.  Much  of  the 
anemia  in  anchylostomiasis  is  referable  to  n)inute  hemorrhages. 

Of  the  depleting  effect  of  albuminous  and  bloody  exudates  goo<l  ex- 
amples are  seen  in  the  acute  anemia  of  exudative  nephritis  (Dieballa), 
and  in  the  hemorrhages  of  the  infectious  purpuras,  tuberculous  pleurisy, 
and  malignant  endocarditis. 

Chronic  suppuration  leads  to  a  peculiar  form  of  cachexia  with  waxy 
changes  in  the  viscera,  and  severe  anemia. 

By  the  interaction  of  these  various  factors  there  usually  results  in 
infectious  diseases  and  cachexias  a  certain  grade  of  secondary  anemia. 
Yet  notwithstanding  the  many  contril)uting  causes,  acute  infectious  dis- 
eases, e.  r/.,  typhoid  fever,  may  run  their  course  with  no  demonstrable 
reduction  in  red  cells,  and  it  is  a  rule  of  frequent  application  that  as- 
sociated conditions  in  these  diseases  obscure  the  actual  state  of  the 
blood  and  tend  to  diminish  or  exaggerate  the  true  degree  of  anemia. 

The  polycythemia  of  cholera  is  an  example  of  one  exti'eme  condition 
of  this  sort,  partially  illustrated  also  by  the  slight  polycythemia  some- 
times observed  in  typhoid  fever. 

In  dropsy  the  state  of  the  blood  accords  with  the  watery  condition 
of  the  tissues,  and  anemia  is  apt  to  be  exaggerated.  Grawitz  has  found 
that  injections  of  extract  of  cancerous  tumor  greatly  accelerate  the  flow 


BIBLIOGRAPHY.  103 

of  lymph  into  the  circulation  and  are  followed  hy  reduction  of  red 
cells. 

The  morphological  changes  in  the  blood  of  secondary  anemias  have 
been  rather  fully  described  in  an  extensive  literature  upon  this  subject 
and  will  be  detailed  later.  Of  the  chemical  changes  very  much  less  is 
known,  although  it  can  readily  be  seen  that  the  varying  prominence 
of  the  above  factors  probably  leads  to  very  different  chemical  altera- 
tions. To  what  extent  constant  chemical  peculiarities  can  be  estab- 
lished for  the  secondary  anemias  of  widely  different  origin,  e.  g.,  hemor- 
rhages, and  syphilis,  remains  to  be  decided,  but  at  present  there  is  no 
evidence  to  show  that  any  uniform  chemical  changes  distinguish  one 
form  of  secondary  anemia  from  another.      (Ehrlich.) 

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CHAPTER   IV. 
THE   LEUCOCYTES    AND    LEUCOCYTOSIS. 

Morphology. 

In  fresh  blood  leucocytes  are  colorless  rather  highly  refractive  bodies 
usually  larger  than  red  cells,  cohering  to  one  another  and  to  the  glass, 
and  exhibiting  a  highly  refractive,  compact,  or,  in  the  large  mononu- 
clear cells,  vesicular  nucleus.  Granules  are  invisible  in  the  normal 
mononuclear  cells  of  the  circulation,  but  in  the  others  minute  opaque 
(neutrophile)  granules  are  distinctly  apparent  in  the  polynuclear  cells, 
and  large  greenish  refractive  granules  serve  to  fully  distinguish  the 
eosinophile  cells.  The  protoplasm  of  the  mononuclear  cells  is  homo- 
geneous, and  refractive  in  the  lymphocytes,  transparent  in  the  large 
mononuclear.  Ameboid  motion  begins  promptly,  especially  on  a  warm 
stage,  in  the  finely  and  coarsely  granular  cells,  becomes  most  active 
usually  after  20-40  minutes  and  may  persist  for  hours.  The  hyaline 
cells  may  protrude  blunt  processes  but  do  not  execute  true  ameboid 
movements.  In  some  later  stages  of  ameboid  activity  the  granules 
may  show  extremely  active,  vibratory,  dancing,  and  swarming  move- 
ments in  cell  bodies  or  processes.  These  have  been  regarded  as 
Brownian  movements  or  as  indicating  structural  changes  of  approach- 
ing death  of  the  cell.  In  many  cells,  especially  in  anemic  blood,  there 
appear  from  the  first  large  and  small  clear  spheroidal  areas  which  on 
staining  appear  to  be  divided  among  watery  vacuoles,  or  granules  of 
fat,  glycogen,  or  other  degenerative  products. 

Varieties  of  Leucocytes. — In  stained  specimens  four  varieties  of 
leucocytes  may  be  distinguished,  viz.: 

1 .  Lymphocytes. 

2.  Large  mononuclear  leucocytes. 

3.  Polynuclear  neutrophile  leucocytes. 

4.  Eosinophile  leucocytes. 

1.  Lymphocytes  are  slightly  smaller  or  larger  than  the  red  cells, 
with  a  narrow  rim  of  strongly  basophile  homogeneous  or  coarsely 
reticulated  protoplasm,  and  a  compact  or  coarsely  reticulated,  spheroidal 
nucleus.  Protoplasmic  granules  are  almost  invariably  absent,  but  in 
most  of  the  larger  cells  the  reticulum  shows  nodal  thickenings  which 
are  sometimes  difficult  to  distinguish  from  protoplasmic  granules.  Like- 
wise the  nuclear  reticulum  may  show  nodal  thickenings  or  circular 
rings  resembling  nucleoli,  but  these  cells  contain  no  true  nucleoli.  (Cf. 
Ehrlich,  Die  Anaemic,  I.,  p.  47.)  While  the  nuclei  of  lymphocytes 
are  usually  spheroidal,  there  occur  in  normal  blood,  and  especially  in 


PLATE    II. 


3     -** 


^>>.-^. 


Normal  Blood.     (Eosin  and  Methylene  Blue.) 


Fig.  I.  Normal  rouleau. 

Fig.  2.  Red  cell,  extruding  slightly  basophilic  (nuclear?)  contents  as  blood  plates. 

Fig.  3.  Lymphocyte. 

Fig.  4.  Large  mononuclear  leucocyte  with  finely  reticular  cytoplasm. 

Fig.  5.  Polynuclear  neutrophile  leucocyte,  granules  unstained. 

Fig  6.  Eosinophile  leucocyte. 


LEUCOCYTES  IN  PATHOLOGICAL  BLOOD.  107 

lymphemia  medium-sized,  strongly  basophilic  hyaline  leucocytes   with 
incurved  or  subdivided  nuclei,  which  must  be  classed  with  lymphocytes. 

2.  Large  mononuclear  leucocytes  may  be  only  slightly  larger  than 
lymphocytes,  but  many  of  them  are  the  largest  cells  seen  in  normal 
blood.  Their  protoplasm  is  slightly  basophile  and  very  finely  reticular, 
with  nodal  thickenings  often  resembling  granules.  Their  nuclei  are 
vesicular,  rather  coarsely  reticulated,  with  one  or  two  central  nodal 
thickenings  resembling  nucleoli,  and  may  be  circular,  or  horseshoe- 
shaped  (transitional  leucocytes),  or  elongated.  In  Ehrlich's  triacid 
solution  the  bodies  of  mononuclear  basophile  cells  stain  very  faintly 
red.     (Plate  I.) 

3.  Polynuclear  ^  leucocytes  are  two  or  three  times  as  large  as  the 
red  cell.  Their  protoplasm  is  reticulated  and  possesses  as  inte- 
gral parts  of  the  reticulum  protoplasmic  neutrophile  granules  in  con- 
siderable number.  The  reticulum  is  otherwise  very  slightly  basophilic 
and  may  be  demonstrated,  with  basophilic  nodal  thickenings,  by 
methylene-blue.  (Plates  IV.,  VI.)  Their  nuclei  are  elongated  and 
constricted,  or  composed  of  two  or  more  lobes  usually  connected  by 
threads  of  chromatin.  These  lobes  ai'e  coarsely  reticulated  and  usually 
possess  a  central  nodal  thickening.  They  may  become  completely 
separated  from  each  other. 

4.  Eosinophile  leucocytes  vary  in  size  from  that  of  lymphocytes  to 
that  of  polynuclear  leucocytes.  Their  protoplasm  contains  large 
strongly  acidophile  granules  which  are  believed  to  be  integral  parts  of 
a  cytoreticulum.  (Heidenhain,  Gulland.)  Their  nuclei  are  coarsely 
reticulated  aud  usually  bilobed,  the  lobes  are  more  often  separate  than 
in  the  neutrophile  cells,  aud  they  stain  rather  faintly  with  nuclear  dyes. 

Leucocytes  in  Pathological  Blood. — Besides  the  above  forms  of 
colorless  cells  w^iich  alone  are  present  in  normal  blood,  other  types  of 
cells  are  seen  in  the  circulation  in  disease.  1.  Myelocytes  are  mono- 
nuclear cells  with  neutrophile  or  with  eosinophile  granules.  Three 
types  of  myelocytes  should  be  distinguished,  (a)  Ehrlich's  mye- 
locyte is  a  medium-sized  cell  with  pale,  usually  central  nucleus, 
and  neutrophile  granules.  It  is  found  in  many  diseased  conditions, 
especially  in  leukemia  and  secondary  anemia.  (Plate  VII.)  (b) 
Corxil's  myelocyte  is  a  large  cell,  much  larger  than  a  poly- 
nuclear leucocyte,  with  pale  eccentric  nucleus  and  neutrophile  gran- 
ules. It  is  found  almost  exclusively  in  myelogenous  leukemia,  and 
less  frequently  in  v.  Jaksch's  anemia.  (Plate  VII.)  (c)  Eosinophile 
MYELOCYTES  may  resemble  the  eosinophile  cells  of  normal  blood  except 
that  their  nuclei  are  single.  Such  cells  are  abundant  in  myelogenous 
leukemia,  occur  not  infrequently  in  v.  Jaksch's  anemia,  and  have  been 
found  in  myxedema  by  Mendel,  in  some  infectious  diseases  by  Turck, 
and  in  pernicious  malaria  by  Bignami.     Or  their  granules  may  be  of 

'  The  attempt  to  displace  Ehrlicli's  old  term  "polynuclear"  by  the  unfortunately 
derived  "polymorphonuclear"  seems  to  tlie  writer  ill-advised.  Tiie  former  designa- 
tion has  become  tirraly  established,  never  leads  to  confusion,  and  seeing  that  polymor- 
phism characterizes  nuclei  of  other  mononuclear  cells,  and  that  the  lobes  of  the  neu- 
trophile cell  are  often  separate,  there  appears  to  be  no  gain  in  accuracy  by  such  a  change. 


108  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

excessive  size,  in  which  case  they  are  pathognomonic  of  myelogenous 
leukemia.     (Plate  VII.) 

2.  Mast-cells  are  mononuclear  or  polynuclear  cells  of  different  sizes, 
whose  characteristic  feature  is  the  presence  of  large  and  small  strongly 
basophile  granules.  These  granules  do  not  reflect  the  pure  color  of 
many  stains  but  are  metachromatic,  especially  with  thionin.  An  iso- 
lated mast-cell  is  not  infrequently  seen  in  normal  blood,  but  when 
present  in  any  considerable  numbers  they  are  pathognomonic  of  myelo- 
genous leukemia.     (Plate  X.,  Fig.  1.) 

The  Classification  of  Leucocytes. 

Although  the  leucocytes  were  discovered  by  Nasse  in  1835  the  first 
scheme  of  classification  based  upon  their  supposed  points  of  origin  was 
offered  by  Yirchow  who  divided  the  colorless  cells  into  lymphocytes 
derived  from  the  lymph-nodes,  splenocytes  from  the  spleen,  while  poly- 
nuclear cells  he  regarded  as  developmental  forms  of  the  mononuclear. 
Similarly,  Einhorn,  a  pupil  of  Ehrlich's,  classed  the  leucocytes  as  :  (1) 
lymphocytes,  small  and  large,  derived  from  the  lymph  nodes,  (2) 
myelogenous  cells  (eosinophiles)  from  the  marrow,  and  (3)  large  mono- 
nuclear, transitional,  and  polynuclear  cells,  from  spleen  or  marrow. 

In  1865  M.  Schultze  described  the  leucocytes  as  (1)  non-granular 
(large  and  small  mononuclears),  (2)  finely  granular  (neutrophiles)  and 
(3)  coarsely  granular  (eosins  and  mast-cells).  He  believed  that  all 
granules  and  cells  represent  developmental  forms  of  one  series. 

Lowit's  classification,  based  on  the  morphology  of  the  nucleus,  in- 
cluded small  and  large  mononuclear  cells  (lymphocytes),  "transitional  " 
leucocytes,  and  polynuclear  leucocytes.  Regarding  solely  the  nucleus, 
Lowit  found  no  difficulty  in  deriving  all  leucocytes  in  one  series  of 
cells.  It  remained  for  Ehrlicli  to  establish  the  essential  distinction  be- 
tween leucocytes  by  demonstrating  specific  microchemical  reactions  in 
the  granules  of  Schultze. 

Ehrlich  divided  the  aniline  dyes  into  three  main  groups.  (1)  Basic 
dyes,  as  hematoxylon,  methylene-blue,  thionin,  etc.,  act  as  bases,  unit- 
ing, with  selective  power  in  the  order  named,  with  the  acid  principles 
of  cells  (nucleinic  acid).  (2)  Acid  dyes,  as  eosin,  fuchsine,  aurantia, 
act  as  acids,  and  unite  with  the  basic  principles  of  cells.  (3)  Neutral 
dyes.  When  certain  basic  and  acid  dyes  are  mixed  a  compound  is 
formed  of  modified  staining  qualities  which  unites  with  certain  cell 
structures  not  readily  stained  by  other  methods.  Such  a  mixture 
Ehrlich  calls  a  neutrophile  stain,  an  example  of  which  is  the  triacid 
mixture.     Neutral  red  seems  also  to  fall  in  this  class. 

According  to  their  reactions  to  these  dyes  the  granules  of  leucocytes 
in  human  blood  may  be  divided  into  three  main  groups,  basophile, 
acidophile  (oxyphile),  and  neutrophile,  and  on  these  grounds  the  present 
classification  of  leucocytes  is  based,  as  follows  : 

1.  Basophile  Cells:  Mast  cells  (j-gramdes).  Granules  strongly 
basophile.  Lymphocytes.  Protoplasm  strongly  basophile.  Large 
MONONUCLEAR  LEUCOCYTES.     Protoplasm  slightly  basophile. 


FINER  STRUCTURE  OF  LEUCOCYTES.  109 

2.  Neutrophile  Cells  :  Polynuclear  leucocytes.  Neutrophile  [e) 
granules.     Myelocytes.     Neutrophile  granules. 

3.  Eosinophile  Cells  :  Eosinophile  leucocytes.  Large  acidophile 
granules,  {a-gramdes.)  Eosinophile  myelocytes.  Large  acidophile 
granules. 

Ehrlich  also  described  granules  which  are  araphophile,  stain  by  both 
basic  and  acid  dyes,  and  are  found  in  some  marrow  cells,  and  o-granules 
which  are  small  basophile  granules  said  to  occur  in  some  mononuclear 
cells. 

It  is  impossible  here  to  consider  all  the  objections  raised  against  the 
specific  quality  of  the  reactions  demonstrated  by  Ehrlich  and  espe- 
cially the  limitations  shown  to  exist  in  the  application  of  his  principles 
to  other  tissue  cells.  At  present  it  must  be  admitted  that  while  there 
are  rather  narrow  limits  between  which  the  reactions  of  granules  may 
vary,  yet  each  class  of  granules  is  peculiar  to  one  cell  and  transitional 
stages  have  not  been  demonstrated,  while  the  separation  of  leucocytes 
according  to  the  chemical  character  of  their  protoplasm  is  a  much 
more  exact  classification  than  one  on  any  other  basis.  While  the 
original  views  attributed  to  Ehrlich  have  suffered  considerable  modifi- 
cation since  it  became  evident  that  the  granules  of  many  tissue  cells 
though  of  variable  composition  may  give  identical  reactions  to  dyes, 
and  that  the  granules  of  the  same  leucocytes  may  stain  differently,  yet 
the  wisdom  of  his  classification  is  shown  by  the  evidence  which  has 
accumulated  regarding  the  significance  of  these  granules. 

Finer  Structure  of  Leucocytes. 

Recent  studies  have  considerably  increased  the  knowledge  of  the 
minute  structure  of  leucocytes. 

For  many  years  opinions  have  been  at  variance  regarding  the  struc- 
ture of  the  protoplasm  of  basophilic  cells.  It  is  now  evident  that  the 
bodies  of  these  cells  show  the  reticular  structure  of  ordinary  protoplasm 
and  that  any  granules  normally  present  in  them  are  fine  nodal  thicken- 
ings of  this  reticulum.  Moreover  such  nodal  thickenings  when  most 
prominent  do  not  have  the  sharp  character  of  the  neutrophile  or  eosin- 
ophile granules,  and  these  cells  are  properly  regarded  as  non-granular. 
It  has  been  shown  by  Arnold,  Gulland,  and  others,  that  the  neutro- 
phile and  eosinophile  granules  are  connected  by  threads  with  the  retic- 
ulum of  their  cells  and  are  thus  integral  parts  of  this  reticulum  (plas- 
matic). 

Under  suitable  conditions,  in  thinly  spread,  rapidly  dried,  densely 
stained  cells,  it  is  apparent  that  the  cytoreticulum  of  large  mononu- 
clear, neutrophile,  and  eosinophile  cells,  is  directly  continuous  with  the 
nuclear  network  and  that  the  clear  space  sometimes  appearing  to  sepa- 
rate nucleus  from  body  is  artificial.       (Gulland.) 

Centrosomcs  have  been  demonstrated  in  the  leucocytes  of  lower  ver- 
tebrates by  Flemming,  Arnold,  Van  der  Stricht,  Hermann,  Heiden- 
hain,  and   in   human  blood  cells  by  Gulland.     These  bodies  show  no 


110  THE  LEUCOCYTES  AND   LEUCOCYTOSIS. 

special  affinity  for  any  dyes  but  are  best  demonstrated  by  basic  stains. 
They  have  been  stained  by  saffraniu  and  gentian-violet  (Flemraing) 
and  by  methylene-bhie  (Gullaud).  In  human  blood  they  are  ex- 
tremely minute  and  their  demonstration  appears  to  be  a  very  uncertain 
undertaking. 

Small  circular  meshes  sometimes  appear  in  the  nuclei  of  lymphocytes, 
as  depicted  by  Ehrlich,  but  while  these  appearances  resemble  nucleoli 
it  does  not  appear  certain  that  their  significance  is  really  such.  The 
only  colorless  cells  in  the  blood  in  which  the  writer  has  been  able  to 
find  distinct  nucleoli  are  endothelia. 

Significance  of  Cell-granules. — The  theory  of  the  higher  significance  of  cell 
granules  was  first  clearly  stated  by  Altmaun,  although  it  was  suggested  by 
Ehrlich  in  his  early  studies  of  the  granules  of  leucocytes.  Instead  of  being 
degenerative  or  excretory  products,  it  is  now  api^arent  that  they  are  a  secre- 
tory product,  and  represent  the  center  of  the  specific  function  of  the  cell. 

Strong  evidence  in  favor  of  this  view  was  furnished  in  the  demonstrations 
by  Heidenhain,  Arnold,  GuUand  and  others,  that  the  granules  are  not  para- 
plastic,  that  is,  loose  particles  separate  from  the  cytoreticulum,  like  fat, 
melanin,  etc.,  but  are  plasmatic,  i.  e.,  integral  parts  of  the  cytoreticulum. 
The  specific  quality  of  the  granules  is  also  indicated  by  their  chemical  and 
tinctorial  reactions.  The  diflfereutial  chemical  characters  of  the  neutrophile 
and  eosinophile  granules  will  be  considered  later.  (See  Chapter  V.)  Al- 
though the  granules  of  every  cell  of  the  same  type  may  not  all  stain  ex- 
actly alike,  yet  when  submitted  to  fine  chemical  tests,  one  cell  is  found  to 
contain  only  one  kind  of  granule.  The  studies  of  Knoll,  Hirschfeld,  Kurloff, 
and  others,  upon  the  leucocytes  of  lower  animals  have  shown  that  the  wander- 
ing cells  of  vertebrates  and  invertebrates  possess  granules  which  are  peculiar 
to  each  animal  and  are  strictly  limited  to  separate  types  of  cells.  Ehrlich 
regards  the  opposite  behavior  of  different  cells  under  different  chemotactic 
influences  as  evidence  of  the  specific  nature  and  function  of  each  variety  of 
leucocyte  and  of  its  peculiar  granule. 

While  the  above  considerations  point  to  the  secretory  nature  of  the 
granules,  the  exact  function  of  the  secretion  has  not  been  demonstrated. 
Altmann  believes  that  they  furnish  oxygen  for  the  metabolic  processes  of 
the  cell.  Ehrlich  once  (1891)  regarded  them  as  a  sort  of  reserve  material 
destined  for  use  within  the  cell,  but  has  not  expressed  himself  recently  on 
this  point.  Hankiu,^  Kanthack,  Hardy  and  Keng,  apply  the  term  alexines 
to  the  secretoiy  granules  of  leucocytes,  and  believe  that  they  are  destined  to 
be  thrown  out  into  plasma  or  lymph  and  to  exert  a  bactericidal  or  antitoxic 
influence.  Sherrington  and  most  observers  cannot  find  sufficient  ground  for 
the  acceptance  of  this  view.  Metchnikoff  i  refers  to  the  granules  as  reserve 
material,  but  does  not  point  out  their  exact  destination. 

Numbers  of  Leucocytes. 

The  first  estimates  of  the  number  of  leucocytes  in  the  cubic  milli- 
meter of  blood  were  made  by  Samuel  and  Welcker  and  were  generally 
accepted  for  some  years.  Malassez,  with  his  improved  method,  con- 
siderably reduced  these  older  figures.  With  the  introduction  of 
Thoma's  instrument  still  more  accurate  estimates  were  secured  which 
remain  undisturbed  at  the  present  time,  and  agree  fully  with  the  more 
recent  results  obtained  by  Rieder,  Reinert,  and  Limbeck. 

The  following  table  is  compiled  from  the  chief  contributions  on  this 
point : 


PROPORTIONS   OF   VARIOUS  FORMS  OF  LEUCOCYTES.        HI 
Observations  on  Normal  Numbers  of  Leucocytes. 

Min. 


Samuel 

Welcker 

Moleschott 

Mahissez  ^ 

Duperie 

Hayeni 

Bouchout,  Dubrisay 

Grancher 

Hirt 


Thoma,  Lyon.... 

Halla 

Tumas 

Sorensen  

Patrigeon 

Eeinecke 

Von  Jakscli 

Limbeck 

-o-  J         f  adults  ... 
Kieder    {    ,  •,  i 

t  children 

Reinert 


j  6  A.  M 
t4P. 


M. 


Average. 

Max. 

14000 

13432 

14925 

14000 

7692 

4545 

6000 

6116 

9000 

f  8388 
15464 

10590 

7066 

7533 

10106 

6200 

9600 

10 

10000 

7351 

7482 

8-9000 

7680 

9600 

9960 

12400 

5125 

8262 

12857 

12605 

3750 


3000 

6784 
4430 
4960 
4800 

2000 


4200 
7200 


In  estimating  the  leucocytes  in  both  health  and  disease  one  is  con- 
fronted by  a  great  variety  of  disturbing  factors,  including  the  causes  of 
distinct  physiological  leucocytosis,  the  individual  peculiarities  of  the 
subject,  and  the  ordinary  variations  in  the  local  condition  of  the  part 
from  which  the  blood  is  taken.  All  that  has  been  said  regarding  ac- 
cidental variations  in  red  cells  applies  equally  to  leucocytes,  and  one 
must  carefully  consider  the  effects  of  vaso-motor  phenomena,  of  changes 
in  the  volume  of  plasma,  and  of  the  presence  of  inflammation  or  edema. 
It  should  be  remembered  that  while  the  leucocytes  remain  nearly  uni- 
form in  the  great  vessels,  their  proportions  in  the  capillary  circulation 
may  change  more  rapidly  thau  those  of  the  red  cells,  owing  probably 
to  chemotactic  influences.  The  most  common  sources  of  error  may  be 
avoided  by  taking  specimens  about  4  hours  after  a  meal,  and  at  the 
same  hour  each  day. 

Proportions  of  Various  Forms  of  Leucocytes. — The  proportions 
of  the  different  forms  of  leucocytes  in  normal  blood  are  even  less  fixed 
than  their  numbers.  Ehrlich's  figures  may  well  serve  as  a  standard 
for  healthy  adults. 

Lymphocytes,  22-25  percent. 

Large  mononuclear  and  transitional  leucocytes,  2-4  per- 
cent. 

POLYNUCLEAR  NEUTROPHILE  LEUCOCYTES,  70-72  percent. 

Eosinophils  cells,  2-4  percent. 

Mast-cells,  .5  percent. 

The  chief  variations  from  these  limits  which  deserve  mention  are 
the  maximum  percentages  given  by  Rieder  for  lymphocytes  (30  per- 
cent) and  by  Limbeck  for  polynuclear  leucocytes  (80  percent).  In 
childhood  the  proportion  of  lymphocytes  is  usually  much  increased 


112  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

(55-66  percent),  and  that  of  polynuclear  cells  correspondingly  dimin- 
ished (28-40  percent).     (Gundobin,  Rieder.) 

Degenerative  Changes  in  Leucocytes. 

While  degenerative  changes  in  leucocytes  have  always  been  recog- 
nized as  necessary  processes  in  degenerating  tissues  in  which  the  leu- 
cocytes were  lodged,  references  to  acute  degenerative  changes  in  leu- 
cocytes of  the  circulating  blood  have  been  so  scanty  as  to  lead  some 
writers  to  deny  their  existence.  It  therefore  becomes  necessary  to 
consider  briefly  the  general  evidence  at  hand  concerning  the  occurrence 
and  significance  of  such  changes  in  circulating  leucocytes. 

It  was  perhaps  Lowit's  claim  that  leucocytolysis  necessarily  precedes 
leucocytosis,  which  called  special  attention  in  recent  years  to  the  de- 
struction of  leucocytes  in  the  circulation.  Although  Lowit's  claim 
cannot  be  fully  supported,  the  fact  that  the  majority  of  leucocytoses 
are  preceded  or  accompanied  by  the  destruction  of  many  leucocytes  in 
the  circulation  has  been  amply  proven  by  the  work  of  Uskoff,  Botkin, 
Gabritschewsky,'Engel,  Klein,  Goldscheiderand  Jacob,  and  many  others. 

E.  Botkin  followed  up  the  subject  in  a  series  of  experimental  and 
clinical  studies  and  showed  that  in  1 -percent  solution  of  peptone  and 
in  the  fresh  plasma  of  various  infectious  diseases,  all  leucocytes  dissolve 
and  disappear  with  varying  rapidity.  The  lymphocytes  proved  most 
resistant.  The  changes  described  bv  Botkin  were  of  an  extensive 
variety  but  the  principal  features  included  the  formation  of  coarse 
granules  in  mononuclear  cells  ;  extrusion  and  loss  of  granules  from 
polynuclear  cells  ;  formation  of  vacuoles  and  clefts  ;  fragmentation  and 
solution  of  cell-bodies  ;  formation  of  blood  plates  ;  swelling,  fading, 
shrinkage,  subdivision  and  final  disappearance  of  nuclei.  Comparing 
these  experimental  changes  with  those  observed  by  himself  or  reported 
by  others  in  infectious  diseases  and  in  leukemia  Botkin  declared  that 
no  examination  of  the  blood  can  he  considered  complete  which  leaves  out 
of  account  the  degenerative  changes  in  leucocytes. 

The  principal  contributions  which  seemed  then  (1896)  to  justify 
Botkin's  claim  were  those  of  Hankin,  who  found  in  the  extrusion  and 
loss  of  granules  of  the  rabbit's  leucocytes  the  source  of  bactericidal 
alexines,  of  Haetaguroff,  who  observed  various  degenerative  changes  in 
the  leucocytes  of  typhoid  fever,  of  Engel,  who  described  a  variety  of 
changes  in  the  leucocytes  of  an  anemic  child,  and  of  Gumprecht,  who 
called  special  attention  to  the  pathological  changes  in  the  leucocytes  of 
leukemia. 

In  1895  the  writer  described  degenerative  changes  in  the  leucocytes 
of  diphtheria.  Similar  lesions  have  since  been  reported  by  File,  who 
regarded  many  of  the  altered  cells  as  dead,  and  by  many  others. 

In  the  absence  of  more  extended  observation  it  seems  best  to  merely 
describe  rather  than  attempt  to  accurately  classify  the  pathological 
changes  in  leucocytes,  yet  a  tentative  classification  may  be  employed 
for  convenience  sake. 


ACUTE  DEGENERATION   OF  LEUCOCYTES.  113 

Acute  Degeneration  of  Leucocytes. — This  process  is  best  demon- 
strated in  acute  infectious  diseases,  especially  in  severe  cases.  As  seen 
in  diphtheria  the  alterations  aifect  both  body  and  nucleus. 

In  diphtheria  the  writer  believed  he  could  detect  an  increased  acido- 
phile  Htain'ing  tendenci/  in  the  neutrophile  granules,  a  conclusion  which 
he  is  disposed  to  retain,  seeing  that  Kanthack  had  previously  found 
that  the  pseudo-eosinophile  granules  of  the  rabbit  may  be  made  to  show 
increased  acidophile  tendency  and  higher  refractive  quality  by  the 
injection  of  minimum  immunizing  doses  of  microbic  poisons.  This  ob- 
servation, however,  has  not  been  further  confirmed.  That  this  change 
when  it  occurs  belongs  in  the  degenerative  series  is  not  clear,  but  it 
may  be  seen  in  cells  which  show  other  distinct  signs  of  degeneration. 

Diminution  in  the  number  of  neutrophile  granules  is  commonly  ob- 
served in  the  polynuclear  cells  in  acute  leucocytosis.  This  abnormality 
may  progress  till  very  few  granules  are  left,  but  their  complete  absence 
is  seen  principally  in  chronic  leukemia.  It  is  usually  associated  with 
marked  nuclear  changes.     Eosinophile  cells  may  be  similarly  altered. 

Swelling  and  fragmentation  of  the  bodies  of  leucocytes  is  commonly 
observed  in  acute  leucocytoses.  It  is  probable  that  many  of  the  torn 
and  distorted  cells  seen  in  dry  preparations  have  undergone  degenera- 
tive changes  which  have  favored  their  complete  destruction  in  smear- 
ing. These  cells  have  been  described  as  "  leucocyte  shadows  "  (Klein), 
a  term  well  suited  to  recall  their  torn  bodies,  scattered  granules,  and 
faded  nuclei. 

The  reticulum  of  large  and  small  mononuclear  cells  in  leukemia  and 
in  severe  acute  toxemia  may  grow  coarser  and  at  times  granular.  Bot- 
kin  has  described  the  appearance  of  granules  in  the  dissolving  lympho- 
cytes of  shed  blood.  Some  of  the  lymphocytes  of  leukemia  appear  to 
be  distinctly  granular.  Ehrlich  depicts  the  separation  of  small  periph- 
eral fragments  of  the  protoplasm  of  lymphocytes.  Globular  projec- 
tions from  such  cells  are  frequently  encountered  but  it  does  not  appear 
certain  that  they  represent  degenerative  plasmoschisis. 

Nuclear  changes  appear  to  be  the  most  significant  of  the  lesions  of 
acute  degeneration  of  leucocytes.  In  fresh  or  dry  specimens  the  nuclei 
stain  less  densely  with  basic  dyes,  their  outlines  are  irregular  and  the 
lobes  shrunken.  The  degeneration  may  follow  the  type  of  karyolysis, 
with  swelling  and  loss  of  chromatin,  or  of  karyorhexis  with  hyper- 
chromatosis  and  subdivision  of  lobes.  (Gumprecht.)  In  acute  leuco- 
cytosis the  former  type  is  more  usual,  but  in  leukemia,  the  latter  form 
is  abundantly  seen.  (See  Plate  IX.)  While  the  lobes  of  the  normal 
polynuclear  leucocytes  are  almost  invariably  connected  with  a  thread 
of  chromatin,  many  of  the  cells  in  severe  acute  leucocytosis  show  com- 
plete subdivision  into  3-6  separate  segments. 

Chronic  Degeneration  of  Leucocytes. — In  diseases  like  leukemia  in 
which  peculiar  chronic  changes  in  white  cells  are  prominent,  many  of 
the  alterations  commonly  seen  in  acute  degeneration  are  also  present. 
Thus,  in  myelogenous  leukemia  one  finds  leucocytes  showing  loss  of 
granules,  presence  of  vacuoles,  granules  of  glycogen,  faded  irregular 


114  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

nuclei,  and  distortion  and  fragmentation  of  cell-bodies.  Some  of  the 
cells  in  leukemic  blood,  however,  exhibit  changes  which  at  least  in 
their  abundance  are  characteristic  of  the  disease  and  which  seem  cer- 
tainly to  be  the  result  of  chronic  processes. 

Complete  loss  of  neutrophile  granules  may  be  observed  in  many 
cells,  both  polynuclear  and  mononuclear,  in  leukemia,  less  frequently 
in  other  conditions.  The  cell  body  remains  slightly  acidophile,  while 
the  nucleus  commonly  shows  degenerative  changes.     (Plate  IX.) 

Complete  subdivision  of  nuclei  of  polynuclear  cells  into  6-1 0  hyper- 
chromatic  segments  is  a  rather  characteristic  appearance  in  leukemic 
blood,  and  is  usually  associated  with  complete  loss  of  granules.  (Plate 
IX.) 

Hydropic  Degeneration. — In  fresh  blood  many  leucocytes  may  be 
found  whose  nuclei  are  indistinct  or  invisible  and  whose  bodies  contain 
many  large  and  small  vacuoles  bounded  by  homogeneous  or  granular 
reticulum.  These  disintegrating  cells  are  specially  abundant  in  ma- 
laria and  leukemia.  In  malarial  blood  when  such  cells  are  pigmented, 
the  prominent  vacuoles,  opaque  granules,  and  streaming  movements 
common  in  dying  protoplasm,  strongly  suggest  the  appearance  of 
vacuolated  parasites.  In  stained  specimens  they  are  found  to  be  com- 
posed of  pale  staining  remnants  of  nuclei.     (See  Plate  VIII.,  Fig. 

3.)  

Hydropic  degeneration  of  nuclei  is  practically  limited  to  some  peculiar 

leucocytes,  both  mononuclear  and  polynuclear,  of  leukemia.      (Plate 

IX.) 

Fatty  degeneration  of  leucocytes  has  often  been  referred  to  as  a  part 
of  the  changes  in  pathological  blood.  The  writer  has  seen  globules  in 
leucocytes  blackening  with  osmic  acid  in  sections  of  blood  in  the  ves- 
sels of  fatty  viscera,  very  rarely  in  circulating  blood.  The  presence 
of  these  globules  in  leucocytes  is  not  a  certain  indication  that  they 
have  resulted  from  the  altered  albuminous  constituents  of  the  cell  nor 
does  it  necessarily  indicate  a  degenerative  process,  so  that  in  the  ab- 
sence of  further  evidence,  the  writer  is  unable  to  include  this  form  of 
degeneration  among  those  affecting  white  blood  cells.  Even  when  fat 
is  abundant  in  the  plasma  the  leucocytes  are  commonly  free  from  it. 
(Gumprecht.) 

Perinuclear  Basophilia. — In  1894  Neusser  (and  later,  Kolisch) 
described  the  appearance  of  basic  staining  granules  about  the  nuclei  of 
polynuclear  and  other  leucocytes,  which  he  termed  as  above  and  claimed 
to  be  a  somewhat  pathognomonic  sign  of  the  uric  acid  diathesis.  At 
the  time  this  observation  was  announced  Lowit  stated  that  perinuclear 
basophilia  was  an  artifact  which  he  had  kept  in  mind  for  some  ten 
years.  Nevertheless  Neusser's  perinuclear  basophilia  brought  consid- 
erable notoriety  to  the  Vienna  school  during  several  years.  Its  lack 
of  clinical  or  pathological  significance  has  been  fully  demonstrated, 
among  others,  by  Futcher,  and  by  Simon. 

Blood-dust.  Hemokonia.— The  older  histologists  have  rather  uniformly 
described  in  normal  plasma  minute  spheroidal  or  spindle-shaped  bodies  of 


SIGNIFICANCE  OF  INFLAMMATORY  LEUCOCYTOSIS.         115 

undetermined  origin.  (Bizzozero,  Landois,  Hayem.)  Eecently  Miiller  2  has 
drawn  special  attention  to  their  occurrence,  describing  them  as  si:)heroidal, 
or  dumb-bell,  or  spindle-shaped  granules  \  to  1  u.  in  diameter,  and  exhibit- 
ing active  Brownian  movements,  but  no  locomotion.  They  are  not  fat, 
being  insoluble  in  alcohol  and  ether  and  not  stainable  with  osmic  acid,  and 
they  appear  to  have  no  connection  with  the  process  of  fibrin-formation. 
Their  identity  with  the  granules  of  leucocytes  was  considered  by  Miiller,  and 
is  claimed  by  Stokes  and  Wegefarth,  who  found  them  to  increase  in  number 
as  the  specimen  stood,  and  observed  that  in  different  animals  their  size  va- 
ried with  that  of  the  granules  of  the  leucocytes.  Nicholls  identifies  them 
with  leucocyte-granules  on  micro-chemical  reactions.  Miiller  found  them 
unusually  abundant  in  a  case  of  Addison's  disease,  and  scanty  in  starvation 
and  cachexia,  but  no  clinical  significance  has  been  demonstrated  for  them. 
If  not  derived  from  leucocytes,  they  may  be  in  part  the  extruded  contents  of 
fragmenting  red  cells,  or  precipitated  albuminous  particles  from  the  plasma. 

LEUCOCYTOSIS. 

Nomenclature. — An  increase  of  leucocytes  distinctly  above  normal 
limits  is  called  leiicocytosis.  When  the  increase  affects  principally  the 
polynuclear  leucocytes,  the  condition  is  termed  polynudear  leucocytosis 
or  simply  leucocytosis.  An  increase  of  lymphocytes  alone  is  called 
lymphocytosis.  Sometimes,  several  varieties  of  cells  are  found  in  in- 
creased numbers,  when  the  term  mixed  leucocytosis  is  used.  Eosino- 
philia  is  perhaps  an  admissible  word  to  designate  an  increase  of  eosino- 
phile  cells. 

A  distinct  diminution  of  leucocytes  is  either  so  phrased,  or  termed 
hypoleuGocytosis,  in  contrast  to  hyperleucocytosis  which  signifies  an  ex- 
cess of  cells. 

Classification  of  Leucocytoses. — Rieder  first  employed  the  follow- 
ing natural  divisions  of  the  subject : 

I.  Physiological  Leucocytoses. 
Leucocytosis  of  digestion. 
Leucocytosis  of  pregnancy. 
Leucocytosis  of  the  new-born. 

II.  Pathological  Leucocytoses. 
Post-hemorrhagic  leucocytosis. 
Cachectic  leucocytosis. 
Ante-mortem  leucocytosis. 
Inflammatory  leucocytosis. 

Each  variety  of  leucocytosis  has  a  somewhat  particular  significance. 
That  of  the  inflammatory  type  will  first  be  considered. 

Significance  of  Inflammatory  Leucocytosis. — It  was  early  seen 
that  the  most  typical  occurrence  of  transient  leucocytosis  is  limited  to 
certain  acute  infectious  diseases  and  here  its  significance  has  been  the 
subject  of  much  study  and  discussion,  the  extent  of  which  has  shown 
this  subject  to  be  one  of  the  broadest  of  biological  problems. 

A  very  simple  illustration  of  a  principle  believed  to  exert  prominent  influ- 
ence in  the  behavior  of  leucocytes  is  found  in  the  actions  of  certain  myxo- 
mycetes  in  the  presence  of  chemicals.  Stahl  found  that  Ethalium  septicum 
placed  on  a  moistened  surface  close  to  a  drop  of  infusion  of  oak  bark  moved 


116  THE  LEUCOCYTES  AND   LEUCOCYTOSIS. 

actively  toward  and  into  the  infusion,  but  moved  actively  away  from  a 
solution  (5-percent)  of  glucose'.  He  also  noted  that  the  plasmocUum  of  Fuligo, 
which  at  first  moves  away  from  a  2- percent  solution  of  salt,  will  later,  if 
needing  water,  advance  and  enter  the  solution.  Pfeifter  called  this  attractive 
and  repulsive  influence  of  chemicals  upon  protozoa  chemotaxis,  and  the 
above  observations  may  serve  to  illustrate  positive  and  negative  chemotaxis 
and  the  transformation  of  a  negative  into  a  positive  chemotaxis.  PfeifFer 
also  extended  these  observations  to  bacteria,  finding  that  nearly  all  nutritive 
substances  exert  a  positive  attraction  for  bacteria,  which  is  determined  not 
by  movements  of  diffusion  of  the  liquids,  but  by  the  specific  nature  of  the 
chemical  substances. 

A  chemotactic  influence  of  bacteria  upon  leucocytes  apart  from  the 
phagocytic  tendencies  of  MetchnikolF  was  pointed  out  by  Peckelharing, 
among  the  first,  who  inserted  beneath  the  skin  of  frogs  pieces  of  parchment 
containing  anthrax,  and  found  them  after  some  hours  surrounded  by  leuco- 
cytes. Gabritschewsky  2  showed  that  the  attractive  agent  was  dissolved  in 
the  fluids  of  these  cultures.  An  extensive  mass  of  observations  has  accumu- 
lated, showing  that  there  is  a  wide  variety  of  bacteria  and  bacterial  and 
chemical  products  which  exert  a  specific  positive  attraction  upon  leucocytes. 
In  some  instances  a  preliminary  repulsion  is  succeeded  by  a  positive  chemo- 
taxis, but  the  examples  of  distinct  negative  chemotaxis  of  bacteria  upon 
leucocytes  are  so  uncertain  as  to  lead  Kanthack  to  conclude  that  probably  no 
bacteria  actually  repel  leucocytes,  though  some  very  rapidly  destroy  the 
attracted  cells,  so  that  the  surrounding  area  is  comparatively  free  from  them. 
An  apparently  clear  example  of  negative  chemotaxis  is  found  in  the  action 
of  the  bacillus  of  chicken-cholera  in  some  susceptible  animals,  while  there 
are  a  great  many  examples  of  failure  of  positive  chemotaxis  {Bacillus  tuber- 
culosis, tyjyhosus). 

A  distinctly  new  element  Avas  added  to  the  knowledge  of  chemotaxis 
when  it  was  first  clearly  shown,  by  Leber,  1  that  chemotactic  action  of  bac- 
teria is  exerted  upon  leucocytes  at  a  distance.  On  placing  within  the  anterior 
chamber  of  the  eye  of  the  rabbit  a  fine  tube  filled  with  a  substance  extracted 
from  cultures  of  Staphylococcus  aureus,  Leber  found  that  the  leucocytes  would 
promptly  overcome  the  action  of  gravity  and  force  a  way  for  a  considerable 
distance  through  lymph  channels,  in  order  to  enter  the  tube. 

The  subject  was  again  considerably  enlarged  in  the  experimental  produc- 
tion of  leucocytosis  by  Limbeck,  who  pointed  out  that  along  with  the  local 
afflux  of  leucocytes  following  subcutaneous  injections  of  bacterial  cultures, 
there  is  a  marked  increase  in  the  general  circulation,  which  in  fact  precedes 
the  local  changes. 

This  action  upon  distant  blood  producing  organs  causing  an  outpour  of 
leucocytes  has  been  variously  interpreted.  It  has  been  referred  by  most 
authors  to  the  direct  chemotactic  action  of  the  virus  distributed  through  the 
circulation.  Limbeck  regarded  the  intravascular  leucocytosis  as  somewhat 
in  the  nature  of  a  forerunner  and  integral  part  of  the  purulent  exudate 
which  gathers  at  the  point  of  inoculation.  Weiss  carries  this  idea  still 
further,  actively  maintaining  that  leucocytes  in  inflammatory  conditions  are 
formed  in  various  tissues  whence  they  pass  into  the  blood.  Leucocytosis  is 
therefore  not  of  uniform  significance  and  origin,  but  is  the  expi'ession  of 
various  underlying  tissue  changes  in  disease.  Lowit  believed  that  the 
increase  of  leucocytes  merely  represents  a  regenerative  effort  on  the  part  of  the 
marrow  to  replace  destroyed  leucocytes,  his  observations  supporting  Virchow's 
original  view  of  the  origin  of  leucocytosis.  Buchner  and  Roraer  also  refer 
leucocytosis  solely  to  the  increased  production  of  cells  under  the  stimulus  of 
bacterial  proteins.  That  an  increased  flow  of  lymph  occurs  in  many  cases  of  in- 
flammatory leucocytosis,  especially  in  that  in  which  the  lymphocytes  are 
increased,  is  indicated  by  the  demonstration  of  a  special  lymphogogic  property 
in  bacterial  proteins.     (Buchner,  Gartner  and  Romer.) 

Schulz,  Rieder,  and  Goldscheider  and  Jacob,  have   held   more   or  less 


SKiSIFICANCE   OF  INFLAMMATORY  LEUCOCYTOSIS.  117 

strictly  to  the  opinion  that  the  leucocytes  are  not  greatly  multiplied  during 
leucocytosis,  but  on  the  contrary  are  merely  overabundant  in  peripheral 
vessels  or  to  a  moderate  extent  are  drawn  into  the  circulation  from  the  depots 
of  ready-formed  cells  in  the  marrow. 

It  is  impossible  here  to  consider  in  detail  the  basis  of  these  various 
hypotheses.  Of  the  hist  mentioned  it  must  be  said  that  there  is  abun- 
dant evidence  both  of  a  new  production  of  leucocytes  in  the  viscera  and 
of  an  increased  outpour  of  these  cells  during  leucocytosis  ;  that  Schulz's 
unconditional  statement  was  erroneous,  and  that  in  so  far  as  later  ob- 
servers have  held  his  views  they  too  remain  in  error. 

Although  the  evidences  of  new  formation  of  leucocytes  in  the  cir- 
culating blood,  lymph  nodes,  and  marrow,  found  by  Schmidt,  Lowit, 
and  Rieder,  seemed  to  them  inadequate  to  account  for  a  great  increase 
in  the  number  of  these  cells,  this  result  may  be  referred  to  the  uncer- 
tainty regarding  the  origin  of  leucocytes,  to  the  mistaken  opinion  that 
polynuclear  leucocytes  are  deriv^ed  from  lymphocytes,  and  to  the  diffi- 
culty of  demonstrating  early  proliferative  changes  in  such  widely  distrib- 
uted fields  as  the  blood  and  marrow.  Yet  Lowit"  could  find  consider- 
ably increased  numbers  of  mitotic  and  amitotic  nuclei  in  circulating 
leucocytes  during  leucocytosis. 

Recent  studies  of  the  marrow  during  experimental  leucocytoses  have 
fully  established  the  existence  of  greatly  increased  cellular  prolifera- 
tion beginning  in  the  early  stages  of  leucocytosis,  and,  in  prolonged 
cases,  completely  transforming  the  histological  appearance  of  this  tissue. 
The  writer  in  1895  compared  the  marrow  of  typhoid  fever  with  that 
of  pneumonia  and  other  exudative  diseases,  in  a  series  of  cases,  and 
found  a  very  striking  difference  in  the  pulp  cords  in  the  two  condi- 
tions, leucocytosis  being  accompanied  by  marked  cellular  hyperplasia, 
affecting  principally  the  neutrophile  myelocytes. 

Rogers  and  Josue  found,  48  hours  after  the  injection  of  Staphylococ- 
cus aureus  into  rabbits,  marked  congestion  and  cellular  hyperplasia  of 
the  marrow  cords  affecting  principally  the  nucleated  red  cells  and 
eosinophiles,  but  by  the  third  day  these  cells  disappeared  and  neutro- 
phile myelocytes  with  many  giant  cells  formed  the  bulk  of  the  now 
greatly  hypertrophied  cords. 

The  sole  ground  that  remains  to  those  who  deny  that  inflammatory 
leucocytosis  is  essentially  a  new  formation  of  leucocytes,  is  the  proba- 
bility that  many  leucocytes  drawn  into  the  circulation  during  the  first 
hours  of  leucocytosis  are  ready-formed  in  the  marrow. 

Of  the  other  hypotheses  it  still  appears  that  each  contributes  a  por- 
tion of  the  truth.  Probably  the  combined  influences  of  chemotaxis, 
and  of  the  new  formation  of  leucocytes  stimulated  by  bacterial  proteins, 
etc.,  are  chiefly  responsible  for  the  general  afflux  of  white  cells.  The 
destruction  of  leucocytes  has  repeatedly  been  shown  to  be  a  subordi- 
nate fiictor  and  entirely  too  slight  to  stimulate  the  production  of  new 
cells  through  ordinary  channels,  as  suggested  by  Lowit. 

Limbeck's  early  belief  in  a  close  connection  between  local  exudate 
and  general  leucocytosis  is  at  least  partially  true,  and  serves  to  empha- 


118  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

size  as  Grawitz  points  out,  that  many  tissues,  to  an  extent,  and  not 
merely  the  blood-forming  organs,  furnish  leucocytes  to  the  circulation. 

In  so  far  as  chemotactic  influences  are  concerned  in  leucocytosis  it 
should  be  remembered  that  the  essential  nature  of  the  attractive  force 
remains  entirely  unknown. 

In  studies  upon  the  visceral  changes  in  leucocytosis  the  writer  be- 
came convinced  that  some  phenomena  now  attributed  to  an  obscure 
chemotactic  influence  may  be  fully  explained  on  purely  mechanical 
principles.  This  statement  applies  especially  to  the  sifting  of  cohesive 
leucocytes  by  swollen  capillary  endothelium,  and  to  a  less  extent  to  the 
outpour  of  new-formed  leucocytes  from  the  marrow,  but  in  the  phe- 
nomena of  local  exudates  other  factors  seem  undoubtedly  to  be  con- 
cerned. 

The  Course  of  Leucocytosis. — The  experimental  study  of  leucocytosis 
has  greatly  increased  the  knowledge  of  the  order  and  significance  of 
the  phenomena  connected  therewith.  It  was  first  observed  by  Werigo 
that  the  inoculation  of  animals  with  bacterial  cultures  is  followed 
within  5-10  minutes  by  a  pronounced  diminution  of  circulating  leu- 
cocytes {hypoleucocytosis),  by  the  deposit  of  the  bacteria  in  the  capil- 
laries of  the  lungs,  liver,  and  other  viscera,  and  by  their  complete  dis- 
appearance from  the  blood. 

Approaching  the  subject  from  another  standpoint  Goldscheider  and 
Jacob,  and  the  writer,  found  that  along  with  the  deposit  of  bacteria, 
the  leucocytes  are  also  sifted  out  of  the  circulation  and  permanently 
lodged  in  visceral  capillaries,  principally  in  the  lungs  and  liver.  The 
writer  also  partially  agreed  with  Lowit  that  actual  destruction  of  leu- 
cocytes follows  such  intravascular  inoculations,  especially  with  large 
doses,  but  did  not  find,  contrary  to  Lowit,  that  leucocytolysis  in  dis- 
ease plays  more  than  a  very  subordinate  part  in  ridding  the  blood  of 
white  cells.  The  initial  hypoleucocytosis  has  been  observed  very  con- 
stantly to  precede  the  appearance  of  leucocytes  in  increased  numbers, 
and  the  same  phenomenon  has  been  observed  in  the  course  of  many 
natural  infections  in  the  human  subject. 

In  experimental  studies  it  has  been  found  that  many  animals  perish 
during  the  stage  of  hypoleucocytosis,  especially  when  an  active  virus  is 
introduced  into  a  susceptible  animal.  Thus  the  inoculation  of  guinea- 
pigs  with  virulent  cultures  of  diphtheria  is  followed  by  death  within  24- 
48  honrs,  duriiig  2^ersistent  hypoleucocytosis,  while  in  the  less  susceptible 
rabbit  the  same  treatment  usually  kills  the  animal  but  not  before  leu- 
cocytosis has  become  well  established.  In  general,  the  increase  of  leu- 
cocytes follows  the  initial  diminution  more  rapidly  in  those  animals  in 
which  the  course  of  the  infection  is  more  favorable.  The  same  rule  is 
found  to  hold  in  the  human  subject,  initial  hypoleucocytosis,  sometimes 
persistent,  having  been  observed  in  malignant  cases  of  pneumonia 
(Kikodse  et  al.),  diphtheria  (Billings),  septicemia,  etc.,  and  its  unfavor- 
able import  in  these  diseases  has  been  fully  demonstrated. 

In  infections  of  ordinary  virulence  hypoleucocytosis  is  established 
within  one-half  to  two  hours  after  the  initial  diminution,  and  Gold- 


SIGNIFICANCE  OF  INFLAMMATORY  LEUCOCYTOSIS.         119 

scheider  and  Jacob  succeeded  in  exciting  pronounced  leucocytosis  with- 
out any  demonstrable  initial  decrease  in  cells.  During  the  course  of 
febrile  reaction  to  exudative  processes,  and  sometimes  during  a  con- 
siderable period  thereafter,  hyperleucocytosis  persists.  The  grade  of 
leiiGocytosis  has  been  found  to  vary  often  with  the  height  of  the  temperature, 
more  closely  with  the  extent  of  the  exudate,  but  as  might  be  expected  from 
its  recognized  significance,  measures  more  exactly  the  reaction  of  the  system, 
to  the  infectious  agent. 

Throughout  the  stages  of  inflammatory  leucocytosis  it  is  the  polynu- 
clear  leucocytes  which  are  chiefly  or  exclusively  concerned  with  the 
process.  During  hypoleucocytosis  these  cells,  and  as  the  writer  finds, 
the  large  mononuclear  cells,  are  greatly  reduced,  having  been  caught 
in  the  capillaries,  while  the  lymphocytes  remain  in  large  proportion. 
Very  soon,  with  the  increase  in  total  numbers,  the  poly  nuclear  cells 
are  found  in  excessive  proportions  (80-95  percent),  and  even  when  the 
total  increase  is  not  great  the  excess  of  polynuclear  cells  is  so  constant 
as  to  furnish  at  times  significant  information  regarding  the  character  of 
the  infection. 

The  hyperemia  and  excitation  of  the  marrow  is  indicated  by  the 
presence  of  normoblasts  (Timof  jewsky)  and  of  a  few  myelocytes  which 
have  now  been  found  in  many  severe  leucocytoses,  especially  in  diph- 
theria (Engel). 

An  absolute  increase  of  lymphocytes,  sometimes  of  extreme  grade,  as 
observed  by  the  writer  in  diphtheria,  is  often  noted  in  the  course  of 
inflammatory  leucocytosis  and  is  to  be  referred  to  special  involvement 
of  lymphoid  tissues. 

Ehrlich  ^  holds  that  while  polynuclear  leucocytosis  is  referable  to 
chemotactic  influences  acting  from  a  distance,  lymphocytosis  is  always 
the  result  of  local  irritation  acting  mechanically.  Relative  or  absolute 
lymphocytosis  is  seen  also  in  digestion  leucocytosis  (Rieder),  in  typhoid 
fever,  with  tumors  of  bone,  and,  in  general,  is  a  frequent  feature  of  in- 
flammatory leucocytosis  in  children. 

During  the  subsidence  of  acute  leucocytosis  the  neutrophile  are 
sometimes  replaced  by  a  considerable  proportion  of  eosinophile  cells, 
as  in  pneumonia,  septic  processes,  etc.  The  significance  of  this  phe- 
nomenon is  entirely  unknown,  but  it  has  been  shown  to  be  of  favor- 
able import. 

The  behavior  of  the  different  cells  in  leucocytosis  is  largely  in  accord 
with  their  known  characteristics  elsewhere.  The  actively  ameboid  and 
phagocytic  cells  are  chiefly  affected,  while  the  non-ameboid  lympho- 
cytes are  much  less  and  only  mechanically  disturbed.  An  exception 
to  this  rule  is  found  in  the  actively  ameboid  eosinophile  cells,  but 
these  are  rarely  found  to  show  phagocytic  qualities.  The  bearing  of 
these  facts  upon  the  significance  of  leucocytosis  will  be  considered 
later. 

Relation  of  Leucocytosis  and  Phagocytosis  to  Immunity. — The  studies 
of  Metchnikoff  upon  phagocytosis  in  lower  animals  have  not  only  es- 
tablished the  great  importance  of  this  process  as  a  protective  measure 


120  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

in  the  protozoa  but  have  gone  far  to  explain  the  significance  of  leiico- 
cytosis  in  the  higher  raetazoa.  There  is  no  room  to  doubt  that  monads, 
for  example,  englobe,  digest  and  destroy  living  threads  of  kptothrix, 
and  the  steps  through  which  Metchnikoff  has  traced  the  process  seem 
to  show  that  in  animals  as  high  as  frogs,  the  leucocytes  alone  are  re- 
sponsible for  the  englobement  and  destruction  of  anthrax  bacilli.  In 
the  higher  vertebrates,  however,  other  factors  may  very  well  super- 
vene, and  before  accepting  the  phagocytic  doctrine  of  leucocytosis  in 
the  human  subject  it  is  necessary  to  consider  in  some  detail  the  extent 
and  limitations  of  the  process  in  higher  vertebrates. 

The  process  of  phagocytosis,  as  described  by  Metchnikoff,  begins  with  the 
cheraotactic  attraction  of  leucocytes  toward  bacteria,  the  englobement  of  the 
germs,  often  in  the  living  virulent  condition,  and  their  digestion  in  stages 
which  may  be  followed  b^'  changes  in  form  and  staining  quality.  The  power 
to  approach  and  englobe  bacteria  is  obviously  found  in  the  ameboid  activity 
of  leucocytes.  The  power  to  digest  bacteria  is  indicated  by  the  morpho- 
logical and  chemical  changes  above  mentioned,  which  include  the  breaking 
up  of  a  bacillus  into  granules  and  its  gradual  loss  of  staining  capacity. 
Moreover  a  digestive  ferment  has  been  demonstrated  in  leucocytes  by  Ross- 
bach,  and  Leber, 2  and  many  investigators,  especially  Buchner,^  have  dem- 
onstrated very  high  bactericidal  power  in  exudates  rich  in  pus.  That  leu- 
cocytes actually  exert  these  bactericidal  powers  in  infectious  diseases  is 
strongly  indicated  by  the  different  behavior  of  these  cells  in  refractory  and 
susceptible  animals.  It  has  been  repeatedly  shown  that  the  leucocytes  of 
susceptible  animals  which  do  not  naturally  attack  certain  bacteria  may  be 
made  to  do  so  by  the  immunization  of  the  animal,  as  in  the  infection  of  mice 
and  guinea-pigs  with  anthrax,  and  pigeons  and  rabbits  with  chicken  cholera. 
That  the  englobed  bacteria  are  alive  and  active  has  been  shown  by  their 
movements  within  the  surrounding  vacuoles  of  the  leucocytes,  and  by  the 
subsequent  development  of  the  englobed  bacteria  when  the  leucocytes  are 
placed  in  bouillon.  (Anthrax  in  pigeons,  Vib.  Metch.  in  immune  guinea-pigs.) 
Indeed,  an  increase  in  virulence  has  been  found  in  cultures  obtained  from 
some  bacteria  passed  through  the  leucocytes  of  refractory  animals.  More- 
over Lubarsch  has  shown  that  frogs'  leucocytes  are  more  actively  attracted 
by  living  bacteria  than  by  the  same  germ  when  dead. 

It  should  be  noted  that  drugs  which  inhibit  the  activities  of  leucocytes 
have  been  found  to  greatly  accelerate  the  spread  of  certain  infections. 
(Opium  in  cholera,  Cantacuzeue.) 

The  histological  study  of  the  reactive  process  at  the  seat  of  inoculation  of 
a  virus  under  various  conditions  has,  also,  furnished  very  strong  support  of 
the  belief  in  the  essential  importance  of  phagocytosis.  It  has  repeatedly 
been  shown  that  in  susceptible  animals  injections  of  highly  virulent  bacteria 
are,  in  general,  followed  by  serous  and  bloody  exudates  which  fail  to  limit 
the  infection  which  becomes  general  and  kills  the  animal,  while  the  same 
treatment  of  immune  animals  is  followed  by  highly  purulent  exudates,  the 
limitation  of  the  infection,  and  recovery.     (Gabritschewsky.^) 

Finally,  the  results  of  minute  study  of  the  behavior  of  various  phagocytes 
should  be  considered.  The  two  actively  phagocytic  leucocytes,  the  polynu- 
clear  neutrophile  and  large  hyaline  cells,  do  not  attack  all  bacteria  in  the 
same  manner.  The  former  are  less  selective,  englobing  nearly  all  forms  of 
bacteria.  Yet  the  bacillus  of  leprosy  is  found  almost  exclusively  witliin  the 
large  hyaline  cells  which  do  not  attack  streptococci  or  gonococci.  Kanthack 
and  Hardy  have  made  important  observations  in  this  field.  Examining  a 
hanging  drop  of  frog's  lymph  inoculated  with  a  few  anthrax  bacilli,  they 
found  that  the  eosinophile  cells  were  first  attracted  to  the  bacilli,  that  they 
discharged  their  granules  upon  coming  into  contact  witli  the  germs,  and  that 


STONIFICANCE  OF  INFLAMMATORY  LEUCOCYTOSIS.         121 

de.s:enerative  changes  soon  appeared  in  the  bacteria.  Later  the  large  hyaline 
ceils  surrounded  the  mass,  the  ox_yphiles  dropped  away,  and  the  altered 
bacteria  were  englobed  and  digested  by  the  hyaline  leucocytes.  These  ob- 
servers found  the  same  division  of  labor  among  leucocytes  in  various  animals 
up  to  man,  the  hyaline  cells  acting  as  phagocytes  of  the  celomic  and  lym- 
phatic systems,  and  the  finely  granular  oxyphile  cells  as  phagocytes  in  the 
hemal  system.  They  ascribe  important  bactericidal  functions  to  the  gran- 
ules of  eosinophile  leucocytes  in  prepai'ing  germs  for  englobemeut  by  the 
ameboid  phagocytes.  Hankin  also  came  to  identical  conclusions  regarding 
the  importance  of  eosinoiihile  cells  in  phagocytosis  in  the  rabbit. 

Based  upon  these  and  many  other  similar  observations,  verified  by 
many  but  actively  combated  by  others,  Metchnikoff  concluded  that 
phagocytosis  is  the  essential  feature  of  inflammation,  and  the  chief  mecha- 
nism in  immunity,  and  gave  exclusively  to  the  leucocytes  and  the  endothelial 
and  other  phagocytic  tissue  cells  a  function  of  vast  importance. 

It  has  been  necessary,  however,  to  modify  the  original  claims  of 
Metchnikoff  in  an  important  particular,  that  an  extracellular  influence 
is  exerted,  upon  bacteria  which  is  sometimes  a  necessary  preliminary  to 
phagocytosis. 

The  steps  by  which  this  fact  has  been  demonstrated  may  be  briefly 
indicated. 

Traube,  Fodor,  and  others,  recognized  that  the  destruction  of  bacteria  in 
the  living  blood  is  often  extremely  active,  and  it  was  suggested  that  the 
fluid  plasma,  and  not  the  leucocytes  and  eudothelia,  is  the  chief  agent  in 
freeing  the  animal  organism  from  infectious  germs.  Grohman  then  demon- 
strated the  bactericidal  action  of  shed  blood.  Nnttall,  next,  found  that  during 
the  process  of  inflammation,  about  the  seat  of  inoculation  in  rabbits  infected 
with  attenuatad  anthrax,  many  bacteria  which  are  not  englobed  nevertheless 
show  degenei'ative  changes,  and  he  also  found  that  blood  serum  and  lymph 
possess  very  active  bactericidal  powers.  These  observations  were  verified  and 
greatly  extended  by  Nissen,  Hankin,  Behring,  Buchner,  and  Vaughan,  who 
have  fully  established  the  presence  both  of  bactericidal  and  of  antitoxic 
principles.  Some  of  these  observers  have  gone  so  far  as  to  deny  any  great 
importance  in  phagocytosis,  and  they  may  be  said  to  represent  the  "  humoral 
theory"  of  immunity. 

It  soon  became  apparent,  however,  that  there  exists  a  very  close  connec- 
tion between  these  "defensive  proteids  "  of  blood  and  exudates,  and  the 
leucocytes.  Hankin,  Buchner,  Kossel,  and  Vaughan  have  shown  that  a 
nucleo  proteid  derived  probably  from  the  nuclei  of  leucocytes  is  the  bacteri- 
cidal agent  in  serum,  exudates,  and  lymph.  This  bactericidal  proteid 
belongs  to  the  class  of  enzymes,  is  extremely  unstable,  is  destroyed  by  heat- 
ing to  55-65°  C. ,  and  has  been  called  by  Buchner  "  alexine."  The  existence 
of  a  distinct  compound  of  this  character  has  not  been  accepted  by  all  phj'si- 
ological  chemists. 

According  to  Hankin,  blood  serum  ordinarily  contains  little  or  none  of 
this  agent,  but  after  the  second  day  of  leucocytosis  it  is  secreted  by  the 
eosinophile  cells  of  rabbit's  blood  or  is  discharged  from  these  cells  during 
defibrination.  Hahn  and  Van  de  Velde  have  shown  rather  conclusively 
that  the  alexines  are  a  secretory  product  of  the  living  leucocyte,  and  are  not 
produced  by  the  destruction  of  these  cells,  although  they  may  be  set  free 
thereby.  Hankin,  Buchner, 3  Hahn,  Bordet,  Shattenfroh,  Bail,  and  others 
have  established  the  essential  relation  between  the  bactericidal  power  of 
exudates  and  their  content  in  leucocytes,  and  have  placed  this  relation  be- 
yond doubt  by  such  demonstrations  as  that  of  Denys  and  Havel,  that  the 
blood  and  exudates  of  dogs  lose  their  bactericidal  power  when  freed  by  fil- 


*?:  1 


122  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

tration  or  the  ceatrifu2:e  from  intact  leucocytes,  but  regain  this  power  when 
the  leucocytes  are  replaced. 

The  controversy  regarding  the  so-called  ^ ^ phenomenon  of  Pfeiffer^^  has 
also  ended  in  a  way  to  favor  the  importance  of  leucocytes  in  the  defense  of 
the  organism.  PfeifFer  found  that  when  cholera  cultures  are  injected  into 
the  peritoneum  of  highly  immunized  guinea-pigs,  the  germs  are  broken  up 
into  granules  and  to  some  extent  dissolved  by  the  peritoneal  fluid  before 
leucocytosis  and  phagocytosis  have  become  fully  established,  but  not,  as 
some  citations  of  this  work  would  lead  one  to  suppose,  before  the  leucocytes 
present  are  actively  engaged  in  phagocytosis. 

Metchnikoff  2  promptly  repeated  this  experiment,  finding  that  the  cholera 
spirillum  flourishes  in  a  hanging  drop  of  the  same  peritoneal  fluid  which  in 
the  body  is  bactericidal,  that  the  peritoneal  fluid  is  really  very  rich  in 
leucocytes,  that  if  a  great  afflux  of  leucocytes  is  previously  excited  by  injec- 
tion of  bouillon  the  phenomenon  of  PfeitFer  is  suppressed,  but  the  germs  are 
englobed  and  destroyed  just  as  quickly  by  the  leucocytes,  and  he  found,  in 
general,  that  the  phenomenon  of  Pfeiffer  occurs  only  in  animals  whose 
leucocytes  possess  very  active  bactericidal  and  phagocytic  qualities,  and 
only  in  those  situations  where  leucocytes  are  or  have  been  abundant. 

The  discovery  of  the  "phenomenon  of  Pfeiffer"  placed  beyond  question 
that  bacteria  may  be  destroyed  by  entirely  extra-cellular  processes,  a  fact 
now  not  infrequently  illustrated  in  the  dissolution  of  bactei  ia  in  Widal's  test. 
While  Metchnikoff"  accepted  this  fact  and  altered  his  views  as  to  the  inva- 
riable necessity  of  phagocytosis,  the  application  of  his  doctrine  was  ex- 
tended rather  than  narrowed,  for  it  still  remains  true  that  the  bactericidal 
principles  are  elaborated  principally  in  the  leucocytes. 

The  foregoing  review  of  the  steps  through  which  the  present  con- 
ception of  phagocytosis  and  immunity  has  been  reached,  while  defec- 
tive in  important  and  highly  interesting  details  has  been  rendered  neces- 
sary in  order  to  set  in  its  proper  light  the  significance  of  inflammatory 
leucocytosis. 

It  is  now  apparent  that  leucocytosis  represents  Nature^s  attempt  to  rid 
the  blood  and  the  system,  by  means  of  leucocytes  and  their  products,  of  the 
bacterial  and  toxic  causes  of  disease. 

It  is  now  possible,  also,  to  understand  the  varying  significance  of 
hypoleucocytosis,  and  to  place  correct  interpretations  on  the  various 
grades  of  hyperleucocytosis  in  infectious  diseases  ;  to  trace  the  relation 
between  local  and  intravascular  leucocytosis,  and  explain  many  of  the 
phenomena  of  exudative  inflammation  ;  to  properly  interpret  the  pre- 
dominance of  mononuclear,  or  of  polynuclear,  and  to  some  extent,  of 
eosinophile  cells,  and  to  recognize  the  specific  quality  of  the  diiferent 
varieties  of  leucocytes  ;  Avhile  the  application  of  all  these  facts  to  ques- 
tions in  general  pathology  has  been  most  extensive. 

Clinical  Types  of  Leucocytosis. 

Digestion  Leucocytosis. — Although  digestion  leucocytosis  was  one 
of  the  earliest  of  observed  phenomena  regarding  leucocytes  (Nasse, 
Yirchow),  owing  to  the  uncertain  methods  employed  by  some  later  ob- 
servers, and  to  the  subsequent  discovery  of  other  marked  physiological 
variations  in  the  numbers  of  the  cells,  the  occurrence  of  a  leucocytosis 
referable  to  digestion  was  not  fully  accepted  until  Pohl,  in  dogs,  and 


DIGESTION  LEUCOGYTOSIS.  123 

Limbeck  and  R.  Muller,  and  Rieder,  in  man,  investigated  the  subject 
with  the  necessary  precautions  against  possible  disturbing  factors. 

It  is  now  evident  that  in  order  to  demonstrate  digestion  leucocytosis 
it  is  necessary  to  know  the  normal  percentage  for  each  individual,  and 
not  to  rely  upon  general  averages,  as  the  effect  of  digestion  is  not 
great,  and  the  leucocytes  at  periods  well  distant  from  meals  vary  con- 
siderably according  to  the  health,  age,  state  of  circulation,  nutrition, 
and  digestion,  of  the  individual.  With  these  precautions  it  has  been 
found  that  a  full  meal  raises  the  number  of  leucocytes  in  the  average 
healthy  subject  about  33  percent  (Rieder),  beginning  certainly  within 
1  hour,  reaching  a  maximum  in  3—4  hours,  and  thereafter  gradually 
declining.  The  exact  figure  reached  cannot  have  much  significance, 
for  the  reasons  above  stated,  but  in  adults  the  maximum  is  not  often 
above  15,000-16,000.  In  healthy  fasting  subjects  the  increase  is 
rarely  over  3,000  cells,  but  in  invalids  the  variations  are  slightly 
greater. 

A  failure  of  digestion  leucocytosis  in  healthy  adults  is  sometimes  ob- 
served and  may  be  referred  to  a  prolongation  of  the  process,  or  to 
chronic  torpidity  of  the  intestines,  or  to  accidental  causes. 

The  quality  of  the  food  has  sometimes  a  distinct  effect  on  the  grade 
of  leucocytosis.  Highly  albuminous  meats,  readily  digested  and  ab- 
sorbed in  considerable  quantity,  have  much  more  influence  upon  leuco- 
cytes than  a  meal  of  vegetables  and  fats.  Indeed,  although  Duperie 
has  reported  digestion  leucocytosis  after  exclusively  vegetable  diet,  it 
is  usually  not  seen  in  any  vegetarian  animal,  probably  because  of 
slower  digestion  and  absorption. 

Of  the  disorders  in  which  digestion  leucocytosis  may  be  expected 
to  fail  the  mildest  are  those  marked  by  torpidity  of  stomach  and 
bowels,  which  lengthens  the  time,  and  diminishes  the  completeness  of 
digestion  and  absorption.  (Rieder.)  R.  Muller  found  it  difficult  to 
excite  leucocytosis  in  anemic  subjects,  except  by  very  large  meals,  until 
the  general  condition  of  the  patient  was  much  improved,  and  Rieder 
also  observed  no  increase  but  even  a  diminution  of  white  cells  in  simi- 
lar cases.  Among  various  hospital  cases  confined  to  bed  from  chronic 
complaints  the  leucocytosis  sometimes  exceeded  the  normal  limits, 
sometimes  was  absent. 

When  from  any  other  cause  the  leucocytes  are  distinctly  increased,  as 
in  pregnancy,  inflammatory  diseases,  etc.,  digestion  usually  fails  to  pro- 
duce a  further  demonstrable  increase. 

In  carcinoma  of  the  stomach,  R.  Muller  first  called  attention  to  the 
absence  of  distinct  digestion  leucocytosis  which  marks  this  condition, 
finding  that  without  regard  to  the  presence  of  HCl  or  pepsin,  these 
cases  do  not  show  a  pronounced  increase  of  leucocytes  after  meals. 
From  later  reports  it  appears  that  about  90  percent  of  cases  of  gastric 
cancer  fail  to  show  any  distinct  digestion  leucocytosis  (2,000-3,000) 
although  there  are  some  clear  exceptions  to  the  rule,  and  more  examples 
of  a  slight  increase.  This  failure  of  leucocytosis  is  apparently  inde- 
pendent of  the  presence  of  HCl  or  pepsin,  occurs  when  stenosis  does 


124  THE  LEUCOCYTES  AND   LEUCOCYTOSIS. 

not  exist,  and  is  referred  by  Schneyer  to  involvement  of  the  neiglibor- 
ing  lymphatics,  and  to  complicating  gastric  catarrh.  In  very  advanced 
cases  it  is  perhaps  invariably  absent.  (Hartnng.)  In  various  other 
conditions  sometimes  simulating  gastric  cancer,  as  benign  stenosis, 
ulcer  of  stomach,  chronic  gastric  catarrh  (Schneyer,  Capps,  Cabot), 
as  well  as  in  carcinoma  of  other  viscera  (Hartnng),  well-marked  di- 
gestion leucocytosis  is  the  rule. 

As  a  dlagnost'iG  test,  the  absence  of  digestion  leucocytosis  has  not 
been  found  to  give  as  reliable  evidence  as  was  first  hoped,  because,  as 
recently  shown  by  Sailer  and  others,  it  is  too  frequently  absent  in 
other  conditions.  As  evidence  against  cancer,  the  presence  of  diges- 
tion leucocytosis  is,  however,  of  considerably  greater  value,  though  by 
no  means  positive.  Nevertheless  the  examination  of  the  blood  de- 
serves a  place  in  the  diagnosis  of  this  often  obscure  disease. 

In  children,  up  to  15  years  of  age,  most  observers  have  found  more 
marked  digestion  leucocytosis  than  in  adults,  especially  after  a  meat 
diet.  (v.  Jaksch,  Rieder.)  The  first  digestive  activity  in  the  new- 
born infant  excites  a  considerable  leucocytosis,  Schiff"  finding  an  in- 
crease to  19,000-27,000  one  hour  after  the  first  nursing,  and  36,- 
000  at  the  end  of  48  hours,  after  several  nursings.  Between  the  tenth 
and  fifteenth  years  Rieder  found  leucocytoses  of  3,000-9,000,  the 
average  increase  being  greater  than  in  adults.  In  the  aged  it  is  some- 
what less  than  in  adults.     (Pohl.) 

Origin  of  Digestion"  Leucocytosis. — The  essential  fiictor  in  di- 
gestion leucocytosis  is,  without  doubt,  the  absorption  of  a  considerable 
quantity  of  albuminous  principles.  This  absorptive  process  has  been 
shown  by  Hoffmeister  to  excite  a  considerable  poliferation  of  mononu- 
clear cells  in  the  adenoid  tissue  throughout  the  gastro-intestinal  tract. 
It  would  seem  that  sucli  increase  of  mononuclear  cells  must  necessarily 
cause  an  increased  number  of  these  cells  to  reach  the  circulation,  and 
Pohl  in  fact,  reported  finding  tlie  mesenteric  veins  during  digestion  in 
dogs,  much  richer  in  leucocytes  both  mononuclear  and  polynuclear 
than  the  arteries.  Rieder,  however,  could  not  find  such  a  dispropor- 
tion between  veins  and  arteries,  and  in  the  absence  of  other  experi- 
mental data  it  becomes  necessary  to  suppose  that  the  marked  increase 
of  lymphocytes  which  characterizes  digestion  leucocytosis  is  referable 
to  an  increased  outpour  of  lymph  from  the  thoracic  duct,  the  occur- 
rence of  which  during  digestion  there  are  obvious  reasons  for  accepting. 

Since  the  proportions  of  mononuclear  and  polynuclear  cells  are  not 
greatly  disturbed  in  digestion  leucocytosis,  the  marrow  must  furnish 
a  considerable  number  of  neutrophile  leucocytes,  and  the  chemotactic 
properties  of  the  absorbed  albumens  must  be  regarded  as  the  chief 
cause  of  their  outpour. 

Regarding  the  exact  proportion  of  different  cells  in  digestion  leuco- 
cytosis data  are  not  numerous  but  sufficient  to  show  that  this  is  a 
*'  mixed  leucocytosis,"  both  lymphocytes  and  polynuclear  cells  being 
increased,  more  especially  the  lymphocytes.  The  eosinophiles  are 
usually  reduced.     (Rieder.) 


LEUCOCYTOSIS  OF  PREGNANCY.  125 

Leucocytosis  of  Pregnancy. — The  occurrence  of  moderate  leucocy- 
tosis  in  the  latter  niontlis  of  pregnancy,  though  previously  known,  was 
first  fully  studied  by  Halla  who  found  a  marked  increase  in  10,  a 
slight  increase  in  6  (12,000-13,000),  and  no  change  in  3,  out  of  19 
cases  examined. 

Rieder  eliminated  any  possible  effects  of  digestion,  allowing  his 
patients  to  fast  16  hours  and  found  a  leucocytosis,  averaging  13,000 
cells,  in  only  21  of  31  cases,  all  the  exceptions  being  multiparte.  Of 
17  multiparse  leucocytosis  was  absent  in  10.  Limbeck  found  11,000 
-13,000  cells  in  each  of  four  cases  examined,  and  Cabot  reports  un- 
usually high  counts  (25,000-37,000)  in  3,  and  the  ordinary  increase 
in  9  cases.  Hubbard  and  White  report  polynuclear  leucocytosis  in 
80  percent  of  their  55  cases,  most  marked  and  constant  in  young 
primiparte.  The  averages  24  hours  before  labor,  were,  primiparge 
15,000,  multipara  11,700.  Before  the  end  of  the  third  month  no 
leucocytosis  is  to  be  expected  (Rieder),  but  the  exact  period  of  its  ap- 
pearance has  not  been  determined.  Rieder  made  the  interesting  ob- 
servation in  six  cases  that  in  the  ninth  mouth  of  first  or  subsequent 
pregnancies,  whether  leucocytosis  exists  or  not,  digestion  causes  a 
diminution  instead  of  an  increase  of  white  cells. 

After  parturition,  the  leucocytes  gradually  diminish,  reaching  the 
normal  usually  in  4-14  days,  but  this  diminution  is  frequently  inter- 
rupted by  slight  disturbances  referable  to  the  repair  of  marked 
erosions  or  tears  of  the  genital  tract,  to  mild  disorders  of  the  breasts, 
and  to  the  loss  of  blood.  During  and  immediately  after  childbirth  a 
considerable  increase  of  leucocytes  has  been  observed  in  a  moderate  num- 
ber of  reported  cases.  (Kosina  and  Eckert,  Malassez,  Fouassier,  Rieder.) 

The  leucocytosis  of  pregnancy  has  been  referred  to  various  causes, 
none  of  which  seem  to  meet  all  the  requirements.  Virchow  found  a 
parallel  between  the  increase  of  leucocytes  and  the  widening  of  the 
uterine  and  abdominal  lymphatic  vessels  and  nodes  and  the  increase  of 
metabolism  in  the  uterus  and  its  contents.  Mochnatschetf 's  compari- 
sons of  the  numbers  of  leucocytes  in  the  finger-blood  and  in  the  cervix 
uteri  do  not  seem  calculated  to  demonstrate  an  increased  supply  of  any 
variety  of  cell  from  the  latter  region.  Limbeck  suggests  that  the 
changes  in  the  breasts  are  the  chief  factor,  recalling  the  round  cell  in- 
filtration which  many  such  glands  show,  as  an  indication  of  very 
active  cellular  processes.  He,  with  others,  have  supposed  that  this 
leucocytosis,  like  that  of  the  new-born,  may  represent  a  continuous 
eifect  of  digestion,  an  opinion  which  cannot  be  accepted  since  digestion 
leucocytosis  is  usually  suppressed  in  late  pregnancy.  Considering  the 
behavior  of  leucocytes  in  general,  it  seems  hardly  a  matter  of  surprise 
that  the  active  cellular  processes  in  the  breasts,  uterus,  vascular  sys- 
tem, and  fetus,  and  the  associated  increase  of  metabolism  should,  when 
instituted  for  the  first  time,  find  a  sympathetic  excitement  in  the  blood- 
producing  organs.  Being  a  "  mixed  leucocytosis,"  with  all  but 
eosinophiles  normally  represented,  this  leucocytosis  is  probably  not 
either  inflammatory  or  toxic. 


126  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

The  Leucocytosis  of  the  New-born. — That  the  blood  of  new-born 
infants  invariably  shows  a  well-marked  leucocytosis  was  noted  by 
many  early  observers,  in  greatest  detail  by  Hayem,  who  found  an 
average  at  birth  of  16,000-18,000,  a  rapid  decrease  to  7,000  toward  the 
third  to  fourth  day,  when  the  initial  loss  of  weight  becomes  most 
marked,  and  a  subsequent  increase  to  9,000-11,000,  with  beginning 
increase  in  body  weight.  In  children  at  8  months  he  found  14,000- 
21,000  white  cells,  while  by  the  fifteenth  month  the  numbers  commonly 
dropped  to  10,000,  and  he  noted  also  that  the  increase  was  largely  in 
the  nature  of  a  lymphocytosis,  the  small  lymphocytes  being  4-5  times  as 
numerous  as  in  adults. 

These  main  features  of  the  leucocytosis  of  the  new-born  appear 
again  in  Rieder's  observations,  who  found  slightly  greater  numbers, 
14,200-27,400,  in  a  few  subjects,  in  whom  the  initial  decrease  on  the 
third  to  fifth  day  was  also  well  marked  and  apparently  unaffected  by 
the  first  demands  on  digestion.  Rieder  found  the  leucocytosis  of  the 
child  uniformly  greater  than  that  of  the  mother,  and,  except  for  the 
preliminary  decrease  of  the  first  week,  much  more  persistent.  His 
differential  counts  show  that  the  lymphocytes  are  not  in  excessive  pro- 
portion at  birth,  but  that  this  excess  becomes  established  later.  (So 
also  Gundobin.)  His  cases  showed  at  birth  a  considerable  excess, 
also,  of  eosinophile  cells. 

Schiff  examined  11  infants  twice  daily  for  two  weeks,  his  results 
showing  excessive  variations  in  the  numbers  of  leucocytes  in  the  first  few 
days  (10,000-36,000),  referable  apparently  to  overfeeding  and  diarrhea. 
The  preliminary  decrease  beginning  on  the  third  to  fifth  days  is  quite 
noticeable  in  his  tables.  At  the  end  of  two  weeks  the  leucocytes  num- 
bered 10,000-15,000. 

Gundobin's  observations  show  that  the  leucocytes  remain  high  dur- 
ing the  first  year  of  infancy  (11,000-14,000),  that  the  excess  of 
lymphocytes  is  established  before  the  tenth  day  and  persists  through- 
out the  first  two  years  (50-65  percent),  when  they  begin  to  decline, 
reaching  the  proportions  of  the  adult  about  the  eighth  to  tenth  year. 

Observations  on  the  Leucocytosis  of  the  New-born. 

Hayem average  for  48  hours 18,000 

"      third  to  fourth  day 7,000 

"      after  fifth  day 9,000-11,000 

Otto ten  to  twenty-five  hours.... 23, 000-25, 000 

Schiff 48  hours 10,000-32,800 

"       fourth  to  eighteenth  day... 12, 000-13,000 

Woino-Oransky..  at  birth 16,980 

"  "        ...14  hours 20,980 

"  "        ...second  day 31,680 

Gundobin last  day,  fetus 8,053 

"         at  birth 19,600 

"         24  hours 23,000 

"         48  hours 17,500 

Kruger one  to  three  days 18,000 

"       after  third  day 15,000 


POST-HEMORRHAGIC  LEUCOCYTOSIS.  127 

Rieder at  birth 14,200-27,400 

"       second  to  fourth  day 8,700-12,400 

"      after  fourth  day 12,400-14,800 

From  the  above  conflicting  reports  it  is  difficult  to  give  precise  de- 
tails regarding  the  leucocytosis  of  the  new-born.  Rieder's  observa- 
tions seem  to  the  writer  the  most  reliable,  in  which  a  moderately  high 
proportion  of  white  cells  is  found  at  birth,  a  distinct  decrease  on  the 
second  to  fourth  day  with  the  diminution  of  weight,  followed  by  a  less 
marked  but  persistent  leucocytosis.  Further  very  careful  studies  are 
needed  in  the  field. 

Regarding  the  origin  of  this  form  of  leucocytosis  opinions  are  at 
variance.  That  the  initial  increase  is  referable  to  concentration  of  the 
blood  and  venous  stasis  seems  to  be  true  both  of  red  and  of  white 
cells.  The  preliminary  decrease  the  writer  believes  to  be  due  to  im- 
provement in  the  venous  circulation  with  relief  of  cyanosis,  and  the 
absorption  of  fluids.  The  subsequent  increase  and  permanent  leucocy- 
tosis of  infancy,  being  largely  a  lymphocytosis  probably  represents  to 
a  considerable  extent  continuous  digestion  leucocytosis.  That  it  is  not 
entirely  referable  to  digestion  is  indicated  by  the  low  counts  found  by 
Rieder  on  the  second  to  fourth  days,  after  frequent  nursing. 

Post-hemorrhagic  Leucocytosis. — A  well-marked  leucocytosis  fol- 
lowing acute  hemorrhage  was  described  by  the  older  writers  (Virchow, 
Nasse,  etc.),  but  the  detailed  study  of  this  condition  was  reserved  until 
Lyon  and  Huhnerfauth  investigated  the  effects  of  hemorrhage  by  the 
newer  methods. 

Huhnerfauth  found  in  9  dogs,  losing  about  4  percent  of  their  body 
weight  by  acute  hemorrhage,  that  the  leucocytes  were  often  slightly 
diminished  immediately  after  the  operation,  much  increased  (maximum 
45,000)  on  the  following  day,  and  that  this  increase  persisted  in  some 
degree  for  two  to  three  weeks.  Lyon,  in  similar  experiments,  also 
found  an  initial  decrease  a  few  minutes  after  the  hemorrhage,  but  soon  a 
very  marked  increase  of  the  white  cells,  reaching  its  highest  point  (62,- 
000)  within  a  few  (6-8)  hours,  declining  rather  rapidly  after  three  to 
four  days,  but  persisting  thereafter  in  moderate  degree  for  days  or  weeks. 
In  the  human  subject  after  a  surgical  operation  attended  with  danger- 
ous hemorrhage,  Lyon  found,  after  one  hour,  41,625  leucocytes,  after 
five  days  14,300,  followed  by  a  slight  increase  for  one  week.  In  a 
case  of  leukemia,  splenectomy  caused  the  leucocytes  to  jump  from  463,- 
000  to  850,000  several  hours  before  death  from  hemorrhage  and  shock. 
Rieder  repeated  the  experiments  on  dogs  finding  the  usual  changes,  as 
a  rule,  but  in  one  instance  a  large  hemorrhage  failed  to  cause  leuco- 
cytosis. In  differential  counts  he  observed  that  most  of  the  leucocytes 
were  poly  nuclear,  finding  as  high  as  97  percent  of  neutrophile  cells 
immediately  after  the  hemorrhage.  In  the  human  subject  he  was  un- 
able to  find  very  pure  examples  of  post-hemorrhagic  leucocytosis,  but  re- 
ported 15,000  cells  after  pulmonary  hemorrhage  in  phthisis  ;  32,600 
(1,300,000  red)  after  hemorrhage  from  cancer  of  the  uterus;  26,500 
(1,985,000  red)  in  ulcer  of  stomach. 


128  THE  LEUCOCYTES  AND  LEUCOGYTOSIS. 

Ill  general,  the  leueooytosis  following  hemorrhage  is  in  proportion  to 
the  extent  and  rapidity  of  the  loss  of  blood,  hut  it  usualli/  disappears  or 
greatly  diminishes  long  before  the  red  cells  are  restored.  The  infusion  of 
fluids  has  been  found  to  considerably  increase  the  leucocytosis.  Tliis 
result  has  been  repeatedly  observed  in  cases  of  splenectomy  (q.  v.). 

The  not  infrequent  failure  of  post-hemorrhagic  leucocytosis  as  re- 
ported by  Rieder,  Stengel,  Cabot,  and  others,  has  not  been  explained. 
In  such  cases  the  remaining  cells  may  be  largely  lymphocytes. 
(Stengel.)  Erb,  however,  reported  marked  absolute  lymphocytosis  after 
hemorrhage. 

It  is  generally  agreed  that  the  chief  factor  in  the  production  of 
post-hemorrhagic  leucocytosis  is  the  outpour  of  lymph  which  restores 
the  lost  bulk  of  blood.  Were  this  the  only  factor,  however,  the  new 
cells  ought  to  be  principally  lymphocytes,  and  the  high  proportion  of 
neutrophile  cells  commonly  seen  points  to  a  special  draining  of  the 
marrow  or  possibly  to  increased  cellular  activity  in  this  tissue.  Against 
this  view  are  the  facts  that  normoblasts  are  not  numerously  present 
till  the  second  to  the  third  day,  while  the  leucocytes  are  most  numer- 
ous after  a  few  hours. 

The  old  opinion  of  Samuel,  Virchow,  and  others,  that  the  more 
cohesive  neutrophile  cells  are  retained  in  the  vessels  is  perhaps  still 
worthy  of  consideration.  After  the  infusion  of  salt  solution  the  high 
percentage  of  polynuclear  cells  can  be  partly  referred  to  the  chemotactic 
influence  of  this  fluid  upon  the  marrow. 

Cachectic  Leucocytosis. — Of  the  varieties  of  leucocytosis  classified 
by  Kieder  that  which  is  frequently  associated  with  severe  anemia  and 
cachexia  is  the  least  homogeneous.  In  its  causation  figure  many  of 
the  conditions  already  shown  to  frequently  excite  leucocytosis,  espe- 
cially loss  of  blood  and  inflammatory  processes.  Yet  there  exists  a 
considerable  group  of  cases  marked  by  continuous  leucocytosis,  in 
which  other  influences  combine  to  increase  the  production  of  white 
cells,  and  to  develop  a  somewhat  peculiar  form  of  leucocytosis  which 
deserves  a  special  description. 

White,  Cruveilhier,  Paget,  and  others  before  them,  who  first  de- 
scribed cachectic  leucocytosis,  regarded  the  excess  of  cells  as  fragments 
of  the  neoplasm.  Andral  and  Gavaret,  Chaillou,  and  Vidal,  recognized 
these  cells  as  leucocytes.  This  correct  interpretation  was  soon  followed 
by  the  more  detailed  study  of  the  condition  by  Lucke,  Sappey,  Nepveu, 
and  especially  by  Hayem,  Alexander,  Schneider,  Pee,  Rein  bach,  and 
Rieder,  each  of  whom  have  contributed  largely  to  the  present  knowledge. 

Some  of  the  clearest  examples  of  this  sort  of  leucocytosis  are  seen  in 
the  cachexia  of  malignant  tumors,  where  the  combination  of  hydremia, 
local  inflammatory  processes,  and  specific  toxemia,  are  the  principal 
factors  concerned. 

Chronic  anemia  may  lead  to  increase  of  leucocytes  in  the  circulation 
through  the  watery  condition  of  the  blood,  the  increased  activity  of  red 
marrow,  here  often  moderately  hyperplastic,  and  the  lowered  blood 
pressure.     Illustrations  of  the  working  of  these  influences  are  seen  in 


CACHECTIC  LEUCOCYTOSIS.  129 

the  increase  of  post-he morrhagic  leucocytosis  after  iafusion,  and  in  the 
periodical  appearance  of  normoblasts  and  mixed  leucocytosis  in  ad- 
vanced chlorotic  anemia.  Yet  chronic  hyperemia  and  extreme  hyper- 
plasia of  the  red  marrow  alone  are  not  necessarily  accompanied  by  leu- 
cocytosis ;  but  often  exist  with  diminished  leucocytes,  as  is  usually  seen 
in  uncomplicated  primary  pernicious  anemia.  So  that  it  is  impossible 
to  ascribe  to  chronic  hydremia  more  than  a  predisposing  influence  in 
cachectic  leucocytosis. 

Horbacewski  and  Lowit^  ascribe  both  the  hydremia  and  the  leuco- 
cytosis of  cachexia  to  the  lymphogogic  and  chemotactic  influence  of  nu- 
cleins  which  in  increased  quantity  are  set  free  by  the  excessive  destruc- 
tion of  tissue  elements,  but  Lowit  claims  from  his  experimental  study 
of  the  subject  that  increased  fiow  of  lymph  alone  is  incapable  of  produc- 
ing leucocytosis. 

Local  inflammations  are  probably  the  most  frequent  causes  of  marked 
cachectic  leucocytosis.  These  may  be  traced  in  the  growing  edges  or 
ulcerating  surfaces  of  malignant  tumors,  in  various  internal  suppurative 
or  necrotic  processes  in  syphilis  and  tuberculosis,  and  in  exacerba- 
tions of  underlying  chronic  inflammations. 

The  special  involvement  of  the  blood-forming  organs  by  neoplasms 
and  inflammations  has  been  found  not  only  to  increase  the  leucocytes 
in  the  circulation  but  at  times  to  give  a  special  character  to  the  leuco- 
cytosis which  may  be  of  diagnostic  service,  e.  g.,  eosinophilia  and 
lymphocytosis  with  sarcoma  of  bone  or  lymph  nodes.  While  sarcoma 
is  usually  attended  with  lymphocytosis,  carcinoma  on  the  other  hand 
usually  excites  a  polynuclear  leucocytosis,  a  difference  which  may  per- 
haps be  referred  to  the  freedom  of  the  lymph  paths  in  the  former  and 
their  occlusion  in  the  latter  case. 

Finally  there  is  to  be  considered  as  the  essential  element  in  cachec- 
tic leucocytosis  a  chronic  toxemia,  which,  in  several  conditions,  is  of  more 
or  less  specific  character. 

Some  importance  here  attaches  to  the  observations  of  Hayem  who 
noted  the  disappearance  of  persistent  leucocytoses  (10,000-21,000)  in 
4  cases  after  removal  of  cancers  of  the  breast,  while  a  recurrence  of 
the  tumor  he  claims  to  have  predicted  from  a  slight  persistent  increase 
of  leucocytes.  Grawitz  has  shown  that  injections  of  extract  of  carci- 
nomatous tissue  and  of  tuberculin  have  a  marked  lymphogogic  effect. 
The  distinct  cachexia  which  often  foreshadows  the  appearance  of  a 
malignant  neoplasm  is  abundant  clinical  evidence  that  these  new 
growths  elaborate  powerful  toxines  but  it  has  never  been  conclu- 
sively shown  that  these  toxines  have  any  particular  influence  upon 
leucocytosis,  which  in  the  majority  of  cases  seems  to  arise  from  other 
factors.  The  same  conclusion  must  be  drawn  from  the  absence  of  any 
uniform  relation  between  cachectic  leucocytosis  and  the  extent  of  miliary 
tubercles  and  guramata,  or  the  extent,  location  and  histological  struc- 
ture of  malignant  tumors.  General  miliary  tuberculosis,  acute  or 
chronic,  usually  fails  to  excite  leucocytosis.  The  writer  has  seen 
severe  anemia  without  leucocytosis,  with  extensive  gummata  in  liver, 
9 


130  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

spleen,  and  thoracic  and  abdominal  lymph  nodes,  and  in  general  car- 
cinomatosis. 

Indeed,  in  a  review  of  many  reported  cases  and  in  the  writer's  own 
experience,  in  the  great  majority  of  cases  of  tertiary  syphilis,  tuberculosis, 
nephritis,  in  a  large  proportion  of  carcinoinata,  and  in  a  rather  smaller 
proportion  of  sarcomata,  cachexia  is  unaccompanied  by  leucocytosis  un- 
less there  is  distinct  local  inflammation,  necrosis,  or  hemorrhage. 

Whence  it  may  be  stated  as  a  general  rule  that  marked  leucocytosis 
in  the  course  of  cachexia,  suggests  a  search  for  one  of  these  complications. 

Ante-mortem  Leucocytosis. — In  1883  Litten  reported  from  sev- 
eral hundred  examinations  of  the  blood  of  40  moribund  cases  in  whom 
no  leucocytosis  had  previously  existed,  that  he  had  found  in  many  a 
more  or  less  pronounced  increase  of  white  cells,  beginning  at  a  varia- 
ble period  before  death. 

When  dissolution  was  rapid  no  leucocytosis  was  found,  but  when 
prolonged,  the  increase  of  white  cells  was  very  marked  (1-5  of  red). 
Litten  was  unable  to  offer  a  plausible  explanation  of  the  phenomenon 
and  failed  to  give  exact  numerical  estimates  and  important  clinical 
details  of  his  cases,  so  that  his  interesting  observations  attracted  but 
little  notice. 

In  1886,  Gottlieb  found  30,000  leucocytes  6  hours  before  death  in  a 
case  of  pernicious  anemia  which  had  previously  shown  no  increase. 

Rieder  found  well-marked  ante-mortem  leucocytosis  in  three  of  four 
cases  in  one  of  which  89.5  percent  of  60,000  cells  were  polynuclear. 
The  case  not  showing  leucocytosis  was  complicated  with  aspiration- 
pneumonia. 

Many  later  reports  of  isolated  observations  on  this  variety  of  leu- 
cocytosis have  proven  the  frequency  of  its  occurrence,  but  have  not 
added  greatly  to  the  knowledge  of  its  special  peculiarities  or  its  sig- 
nificance. 

It  appears  most  probable  that  a  considerable  variety  of  factors  is 
concerned  in  the  ante-mortem  increase  of  leucocytes.  Cohnheim's 
theory,  that  diminishing  blood  pressure  causes  an  increased  outpour  of 
lymph  is  supported  by  the  occurrence  of  post-hemorrhagic  leucocytosis, 
but  not  by  the  high  percentage  of  polynuclear  cells  and  of  nucleated 
red  cells  usually  present.  Litten's  suggestion  that  there  is  an  unequal 
distribution  of  leucocytes  in  favor  of  the  peripheral  capillaries  is  in 
accord  with  the  known  effects  of  stasis.  Limbeck's  opinion  that  ante- 
mortem  leucocytosis  probably  results  in  most  cases  from  terminal  in- 
fections may  certainly  apply  to  many  instances  marked  by  excess  of 
polynuclear  cells,  but  not  to  all,  especially  to  those  rare  cases  showing 
lymphocytosis. 

The  character  of  ante-mortem  leucocytosis  seems  to  depend  largely 
upon  the  precedent  condition.  In  leukemia  and  inflammatory  diseases 
the  cells  principally  increased  are  the  polynuclear  forms  of  the  mar- 
row, and  along  with  these  many  nucleated  red  cells  and  some  mye- 
locytes are  commonly  drawn  into  the  circulation.  In  the  terminal 
stages  of  lymphatic  leukemia  tlie  lymphocytes  may  be  greatly  increased. 


EXPERIMENTAL  LEUCOCYTOSIS.  131 

Pronounced  ante-mortem  lymphocytosis  has  been  seen  in  pernicious 
anemia  by  Cabot  and  by  the  writer,  in  diphtheria  and  other  conditions 
in  children,  in  typhoid  fever,  and  to  a  less  extent  in  malaria. 

It  would  seem  that  the  effects  of  terminal  inflammations,  ante- 
mortem  dissemination  of  intestinal  and  other  bacteria,  ante-mortem 
hyperpyrexia,  vaso-motor  paresis,  serous  exudates,  diarrhea,  lack  of 
fluids  ordinarily  ingested,  etc.,  have  not  received  sufficient  attention  in 
this  important  field,  and  that  the  entire  subject  needs  investigation  on 
a  much  more  elaborate  scale  than  has  yet  been  attempted. 

Experimental  Leucocytosis.  1.  By  Drugs  and  Chemicals. — 
The  earliest  observations  on  experimental  leucocytosis  were  those  of 
Hirt  who,  in  1856,  reported  an  increase  (100-300  percent)  of  white 
cells  following  the  administration  of  Tr.  ferri  pom.,  Tr.  myrrh.,  etc. 
The  same  effect  was  noted  by  Meyer  from  turpentine,  camphor,  and 
oil  of  peppermint.  Later  Pohl,  in  the  endeavor  to  explain  the  origin 
of  digestion  leucocytosis  tested  the  effects  of  a  large  number  of  drugs, 
finding  that  the  aromatic  extracts  and  oils,  vegetable  bitters,  certain 
alkaloids  (piperin,  strychnia,  and  others)  caused  a  rather  distinct  (-10— 
120  percent)  leucocytosis,  when  administered  to  fasting  dogs.  Alco- 
hols, salts  of  various  alkalis,  lead  acetate,  cupric  sulphate,  calomel, 
caffeine,  and  quinine,  he  found  to  be  inert,  and  oxide  of  iron  usually 
so.  In  general  these  leucocytoses  appeared  within  one-half  hour  and 
disappeared  in  two  hours,  and  were  therefore  less  marked  and  per- 
sistent than  those  excited  by  the  absorption  of  digested  albumens. 

Repeating  these  experiments  on  man,  Binz  and  Limbeck  induced 
leucocytoses  by  means  of  camphor  and  oils  of  cinnamon,  peppermint, 
and  anise,  but  Rieder  found  it  impossible  to  secure  much  effect  from 
extract  of  gentian  or  tincture  of  myrrh.  Even  such  a  bland  fluid  as 
solution  of  common  salt  in  subcutaneous  injection  has  been  shown  to 
excite  transitory  leucocytosis.     (Lowit,  Rieder.) 

Bernard,  and  Meyer  and  Seegen  found  the  leucocytes  doubled  after 
the  administration  of  20  gt.  of  ether. 

Horbaczewski "  found  a  moderate  diminution  of  leucocytes  in  man 
after  administration  of  quinine  and  of  atropine,  and  a  considerable  in- 
crease from  antipyrine,  antifebrine,  and  pilocarpine.  The  writer  has 
failed  entirely  to  produce  distinct  leucocytosis  in  rabbits  by  use  of 
pilocarpine. 

Winternitz  studied  the  effects  of  a  great  variety  of  drugs  with 
special  reference  to  the  relation  between  the  grade  of  local  inflamma- 
tion and  the  degree  of  intravascular  leucocytosis.  He  divided  these 
agents  into  two  classes,  one  of  which,  including  salts  and  simple  irri- 
tants such  as  free  acids  and  alkalies,  by  subcutaneous  injection,  induced 
slight  local  disturbance,  and  moderate  leucocytosis  and  fever,  while  the 
other,  including  vesicants,  sapotoxin,  digitoxin,  silver  nitrate,  copper 
sulphate,  mercurials,  and  antimonials,  produced  aseptic  suppuration 
and  higher  leucocytosis.  He  therefore  established  for  these  agents  the 
same  relation  between  local  reaction  and  general  leucocytosis  that  Lim- 
beck has  shown  for  bacterial  cultures. 


r 


132  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

2.  By  Bacterial  Cultures. — Limbeck  injected  cultures  of  bac- 
teria into  the  knee-joints  of  fasting  dogs,  and  found  the  maximum 
leucocytosis  at  the  end  of  6-24  hours,  2-3  times  the  normal  numbers 
being  commonly  reached,  and  88-93  percent  of  the  cells  being  poly- 
nuclear.  The  pyogenic  staphylococci  were  most  active,  increasing  the 
leucocytes  6-7  fold ;  streptococcus  pyogenes  came  next,  and  Fried- 
lander's  pneumobacillus  third,  in  effectiveness. 

Rieder  repeated  these  experiments  using  cultures  from  solid  media 
only.  He  showed  that  such  material  was  very  much  less  active  in 
producing  leucocytosis  than  are  the  fluid  cultures,  that  the  increase  is 
preceded  by  a  transient  decrease  of  cells,  and  that  the  injections  may 
be  followed  by  persistent  hypoleucocytosis  and  death  of  the  animal. 

A  sufficient  number  of  observations  have  since  shown  that  practically 
all  pathogenic  bacteria  in  subcutaneous  or  intravenous  injection  exert 
positive  chemotactic  influence  upon  leucocytes.  The  duration  of  the 
period  of  diminution  and  the  degree  of  subsequent  increase  of  leuco- 
cytes vary  considerably  with  different  species,  cultures,  and  individuals. 

3.  By  Bacterial  Proteins,  etc. — After  Limbeck's  demonstra- 
tion of  the  chemotactic  effects  of  bacterial  cultures,  it  was  soon  shown 
that  various  bacterial  and  other  extracts  are  equally  powerful  excitants 
of  leucocytosis,  as  cadaverin,  putrescin,  ptomaines  of  decomposing 
flesh,  extracts  of  sterilized  cultures  of  staphylococci,  and  phlogosin,  a 
crystalline  alkaloid  obtained  from  similar  cultures.  (Scheurlen, 
Grawitz,^  Behring,^  Arloing,  Leber.* ) 

The  more  complete  separation  of  the  active  chemotactic  principles 
of  bacterial  cultures  was  accomplished  by  Buchner  following  Nencki's 
method.  Buchner  found  that  the  leucocytes  are  influenced  solely  by 
the  albuminous  principles  of  bacterial  cultures  and  these  he  isolated 
from  a  considerable  number  of  species,  in  the  form  of  bacterial  "  pro- 
teins." From  Bacillus  pyocyaneus  he  secured  a  protein  which,  after 
4  daily  doses  of  2  grams,  increased  the  leucocytes  seven-fold.  Testing 
the  effects  of  the  decomposition-products  of  animal  tissue,  peptone, 
alkali-albumen,  and  calcium,  he  found  these  agents  comparatively 
inactive  and  concluded  that  the  principles  derived  from  inflamed  tissue 
are  unimportant  adjuncts  to  the  bacterial  proteins  in  exciting  inflam- 
matory leucocytosis. 

Koch's  tuberculin  was  early  shown  to  cause  at  the  height  of  the 
reaction  a  moderate  and  rather  transitory  increase  of  polynuclear  leuco- 
cytes and  a  simultaneous  diminution  of  eosins.  (Uskow,  Tschisto- 
vitch,  Zappert.)  Botkin  found  it  impossible  to  increase  the  effects  by 
repeated  daily  doses.  A  marked  and  persistent  increase  of  eosinophile 
cells,  reaching  in  one  case  85  percent,  and  in  another  continuing  for 
ten  weeks,  following  the  febrile  reaction  and  frequently  associated 
with  cutaneous  eruptions,  has  been  noted  by  Grawitz,'  Neusser,^  Canon, 
Botkin,^  and  Zappert. 

A  recent  extensive  study  by  Liebmann  indicates  that  tuberculin  is 
positively  chemotactic  to  both  leucocytes  and  the  tubercle  bacillus, 
drawing  each  into  the  circulation,  in  both   man  and  animals.      Lieb- 


EXPERIMENTAL  LEUCOCYTOSIS.  133 

mann  could  find  no  great  uniformity  in  the  behavior  of  eosinophile 
cells,  but  in  rabbits  and  guinea-pigs  tuberculin  caused  a  marked  in- 
crease of  neutrophile  cells,  a  moderate  increase  of  mononuclear  leuco- 
cytes, and  the  appearance  of  a  moderate  number  of  mast-cells. 

That  leucocytosis  follows  the  injection  of  a  great  variety  of  bacterial 
filtrates  and  extracts  has  been  shown  also  by  a  large  number  of  later 
experiments.  The  grade  of  leucocytosis  varies  considerably,  depending 
on  the  quantity  and  virulence  of  the  toxine,  and  the  susceptibility  of 
the  animal. 

Rieder  found  the  leucocytes  increased  twelve-fold  after  three  daily 
injections  of  pyocyanin.  Occasionally  one  encounters  persistent  hypo- 
leucocytosis,  as  did  Romer  after  using  large  injections. 

4.  By  Various  Organic  Principles. — The  Dorpat  school  first 
studied  the  effect  upon  leucocytes  of  another  group  of  agents,  including 
several  animal  principles.  They  found  hypoleucocytosis  followed  by 
hyperleucocytosis  in  marked  degree  after  the  injection  of  fibrin  ferment, 
pepsin,  peptone,  hemoglobin,  decomposing  albuminous  fluids,  pus,  and 
crushed  lymphoid  tissue.  (Hirt,  Bojanus,  Hoffman,  Himmelstjerna, 
Heyl,  Groth.) 

Lowit  studied  the  effects  of  various  albuminous  and  organic  prin- 
ciples, injected  into  animals,  finding  hypoleucocytosis  followed  by  vary- 
ing grades  of  hyperleucocytosis  from  hemi-albumose,  peptone,  pepsin, 
nucleinic  acid,  nuclein,  urea,  sodium  urate,  curare,  and  pyocyanin  and 
tuberculin. 

Vegetable  albumens  were  first  used  to  excite  local  purulent  exudates 
by  Buchner,  who  obtained  aseptic  pus  in  large  quantities  by  the  injec- 
tion into  the  pleura  of  ground  wheat,  pus,  fossil  earth,  and  gluten- 
casein.  Rieder  and  Hahn  also  secured  a  high  grade  of  leucocytosis  by 
the  same  agents. 

Goldscheider  and  Jacob  proceeded  still  further  in  the  study  of  the 
chemotactic  properties  of  animal  extracts  finding  powerful  effects  from 
the  injection  of  glycerine  extracts  of  spleen,  thymus,  and  marrow,  but 
none  from  extracts  of  thyroid,  liver,  kidney,  and  pancreas. 

Applications  of  Experimental  Leucocytosis. — In  1894  Paw- 
lowsky  reported  that  he  had  saved  animals  from  fatal  doses  of  anthrax 
by  injections  of  papayotin,  abrin,  and  ricin,  which  are  very  active  ex- 
citants of  leucocytosis,  and  he  recommended  that  anthrax  in  man  be 
treated  by  local  injection  of  these  agents.  In  guinea-pigs  and  rabbits 
in  which  leucocytoses  had  been  excited  by  papayotin,  or  better  by 
abrin,  injections  of  tubercle  bacilli  were  less  frequently  followed  by 
generalization  of  the  tuberculous  process,  sometimes  by  greater  ten- 
dency to  fibrous  growth  in  the  tubercles,  or  even  by  total  disappearance 
of  tubercles  already  existing. 

In  1895  Lowy  and  Richter  reported  that  rabbits  in  which  they  had 
established  marked  leucocytosis  by  repeated  injections  of  "  spermin  " 
withstood  injections  of  pneumococcus  cultures  3—4  times  as  large  as 
were  required  to  kill  control  animals.  The  therapeutic  effect  was 
much  less  marked  when  the  bacterial  injections  followed  those  of 
spermin  within  24  hours  or  less. 


134  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

Goldscheider  and  Mnller  then  took  occasion  to  recall  some  unsuc- 
cessful experiments  of  their  own  performed  on  guinea-pigs,  in  which 
leucocvtosis  had  been  excited  by  injections  of  splenic  pulp  extract. 
This  procedure  they  had  found  to  yield  no  therapeutic  influence  on  in- 
fections by  Bacillus  diphtherim,  tetani,  proteus,  or  pneumococcus. 

Goldscheider  and  Jacob  had  also  previously  attempted,  without 
success,  to  favorably  influence  by  artificial  leucocytosis  the  course  of 
typhoid  fever  and  puerperal  sepsis. 

In  animals  which  had  received  injections  of  albumoses  Jacob  found 
that  subsequent  infection  with  virulent  bacterial  cultures  was  better 
withstood  if  the  infection  occurred  Avhen  the  leucocytes  were  on  the 
increase  from  the  previous  injection  of  albumose,  but  when  the  in- 
fection occurred  in  the  stage  of  hypoleucocytosis,  it  was  more  rapidly 
fatal  than  in  the  control  animals.  Considerable  therapeutic  effect  was 
apparently  obtained  when  the  administration  of  albumose  occurred 
during  the  increase  of  leucocytes  resulting  from  the  bacterial  injection. 

Hahn  was  able  to  retard  the  progress  of  anthrax  infection  in  rabbits 
by  previously  exciting  leucocytosis  by  means  of  albumoses,  but  with  a 
few  favorable  results  were  a  larger  number  of  failures.  He  went  on 
to  show  that  the  bactericidal  action  of  blood  both  in  man  and  animals 
is  increased  during  the  stage  of  hyperleucocytosis. 

From  the  foregoing  studies  it  is  evident  that  there  is  a  rational 
basis  for  the  employment  of  artificial  leucocytosis  in  the  treatment  of 
some  infectious  processes,  since  both  the  phagocytic  and  bactericidal 
powers  of  the  blood  are  thereby  increased.  Yet  the  results  in  man 
are  as  yet  not  very  favorable,  since  there  is  no  known  method  of  ex- 
citing with  impunity  continuous  leucocytosis  in  the  human  subject. 
The  limitation  of  puerperal  septicemia  by  exciting  localized  abscesses 
by  injections  of  vesicants,  the  extrusion  of  inoperable  malignant  tumors 
by  erysipelas,  and  the  treatment  of  typhoid  fever  with  pyocyanin,  il- 
lustrate some  of  the  practical  difficulties  in  the  way  of  this  branch  of 
therapeutics. 

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136  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

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PATHOLOGICAL    VARLiTIONS.  137 

THE    OCCURRENCE    OF    EOSINS,  MAST-CELLS, 
MYELOCYTES,  AND    LYMPHOCYTES. 

EOSINOPHILIA. 

Physiological  Variations. — The  number  of  eosinophile  cells  in  the 
blood  of  healthy  adults  varies  according  to  Zappert,  between  55-784 
per  cubic  millimeter  (.67-11  percent),  but  in  the  majority  of  indi- 
viduals the  limits  are  between  1-4  percent.  Zappert  regards  50-100 
per  cmm.  as  a  low  normal  count,  100-200  as  intermediate,  200-300  as 
high  normal,  and  over  300  as  pathological. 

In  children  a  relatively  high  proportion  of  eosinophile  cells  is  the 
rule,  and  the  variations  in  number  are  slightly  greater.  The  average 
appears  to  be  about  1-2  percent  greater  than  in  adults. 

There  are  no  uniform  changes  referable  to  old  age,  sex,  pregnancy, 
menstruation,  or  digestion.  A  slight  increase  after  coitus  has  been  ob- 
served. 

Pathological  Variations. — From  the  fact  that  eosinophile  cells  may 
be  multiplied  many  times  without  passing  the  limits  established  as 
physiological,  it  is  obvious  that  none  but  considerable  changes  in  their 
absolute  numbers  can  have  any  distinct  pathological  significance.  Yet 
the  observations  on  eosinophilia  have  referred  quite  as  much  to  per- 
sistently high  or  low  averages  within  normal  limits,  as  to  distinct  in- 
crease or  decrease ;  and  a  certain  pathological  significance  has  been 
shown  to  go  with  these  lesser  variations. 

Diseases  of  the  Blood. — In  leukemia  the  presence  of  large  numbers 
of  eosins  was  first  regarded  by  Ehrlich  as  the  pathognomonic  sign  of 
myelogenous  leukemia,  but  it  has  since  been  shown  that  eosinophilia 
may  be  very  marked  in  other  conditions,  and  that  the  proportion  of 
these  cells  in  leukemia  almost  invariably  lies  within  normal  limits  (1—7 
percent).  Their  total  numbers  however  are  very  greatly  increased, 
Rieder's  highest  estimate  reaching  29,000  per  cmm.  In  lymphatic 
leukemia  they  are  commonly  absent. 

The  presence  of  eosinophile  myelocytes  was  regarded  by  Muller  and 
Rieder  as  pathognomonic  of  leukemia,  but  these  cells  are  not  infre- 
quently found  in  other  conditions.  The  writer  finds  that  very  large 
darkly-staining  eosinophile  granules  in  mononuclear  cells  are  practi- 
cally limited  to  leukemic  blood,  but  isolated  examples  have  been  seen 
in  malaria.     (Bignami.) 

In  chlorosis,  the  eosins  may  be  moderately  increased,  normal,  or 
much  diminished.  Zappert  was  unable  to  verify  Neusser's  belief  that 
absence  of  eosins  in  chlorosis  is  of  unfavorable  import. 

In  secondary  anemia  the  occurrence  of  eosinophile  cells  depends 
largely  upon  the  underlying  condition,  the  anemia  itself  not  effecting  any 
increase  but  rather  a  decrease.  There  are,  however,  many  examples 
of  secondary  anemia  with  marked  eosinophilia,  e.  g.,  anchylostomiasis. 

Diseases  of  Lungs. — The  occurrence  of  large  numbers  of  eosinophile 
cells  in  the  blood  and  sputum  of  asthmatics  was  first  noted  by  Gollasch 


138  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

and  has  been  uniformly  confirmed  by  later  observers  (Leyden,  Zap- 
pert,  Mandybur,  Weiss,  Gabritschewski),  who  have  found  them  to  vary 
in  the  blood  of  such  cases  from  9-22  percent.  In  simple  emphysema 
they  are  not  markedly  increased,  and  in  pulmonary  tuberculosis  they 
are  usually  much  diminished.  Where  tuberculosis  complicates  emphy- 
sema both  blood  and  sputum  may,  however,  show  an  excess  of  eosino- 
phile  cells.     (Weiss,  Aronson  and  Philip.) 

In  tuberculosis  of  lungs  or  other  tissues,  an  absence  of  eosinophile 
cells  from  the  blood  is  often  observed,  and  this  fact  has  been  of  con- 
siderable value  in  differential  diagnosis  between  this  and  other  con- 
ditions in  which  normal  or  increased  numbers  of  these  cells  are  present. 
Yet  when  tuberculosis  is  accompanied  by  cachexia  and  irregular 
suppuration,  eosinophile  cells  may  reappear  in  moderate  numbers. 
Neusser  believes  that  when  eosins  persist  in  tuberculosis,  the  outcome 
is  usually  favorable,  since  gouty  subjects  are  comparatively  resistant 
to  this  infection.  Yet  tuberculosis  in  emphysematous  lungs  is  not  in- 
frequently seen  at  autopsy.  The  eosinophilia  following  injections  of 
tuberculin  has  already  been  considered. 

In  febrile  diseases  of  liver  and  gastro-intestinal  tract  the  occurrence 
of  eosinophile  cells  in  the  blood  shows  no  uniformity.  They  have 
been  found  moderately  increased  in  cirrhosis  of  liver. 

In  chronic  nephritis  the  eosins  are  apt  to  reach  the  higher  physiolog- 
ical limits.  Neusser  believes  that  uremic  seizures  are  regularly  ac- 
companied by  increase  of  eosins  in  the  blood,  and  Zappert  and 
Castellino  report  such  cases. 

In  nervous  diseases,  functional  and  organic,  Zappert  found,  as  a 
rule,  a  moderate  increase  of  eosinophile  cells,  without  being  able  to 
substantiate  Neusser's  classification  of  neuroses  into  those  with  and 
those  without  eosinophilia.  Tlie  latter  he  preferred  to  regard  as  ex- 
ceptions to  the  very  general  rule.  In  a  distinct  sympathetic  neurosis, 
the  eosins  were  not  increased.  In  general  insanity  no  uniform  in- 
crease of  eosins  has  been  demonstrated.  (Zappert,  Krypiakiewicz.) 
Jelliffe  found  a  moderate  increase  in  one,  and  a  total  absence  of  eosins 
in  five  of  twenty  cases  of  general  paresis.  In  Basedow's  disease  the 
eosins  are  usually  increased.     (Neusser.) 

Neusser  finds  an  increase  of  eosins  in  a  variety  of  nervous  disor- 
ders, the  psychoses  of  menstruation,  puerperal  mania,  epilepsy,  tetany, 
Basedow's  disease,  hemicrania.  In  acute  mania  not  connected  with 
pregnancy,  and  in  melancholia,  Somers  found  a  well-marked  and  uni- 
form eosinophilia. 

Tumors. — From  observations  on  24  cases  Zappert  concluded  that  a 
very  uncertain  eosinophilia  may  occur  with  new  growths,  especially 
when  cachexia  is  not  advanced.  He  found  17.76  percent  of  eosins  in 
one  of  several  cases  of  lymphosarcoma,  and  a  distinct  increase  in 
isolated  cases  of  carcinoma.  Neusser  claims  that  eosinophilia  arising 
in  the  course  of  a  tumor  growth  indicates  metastasis  in  the  marrow, 
and  Reinbach  found  60,000  eosins  in  a  case  of  lymphosarcoma  with 
metastasis  in  the  marrow. 


PATHOLOGICAL    VARIATIONS.  139 

Skin  Diseases. — Various  cutaneous  lesions  have  furnished  some  of 
the  most  marked  and  interesting  examples  of  eosinophilia.  While  the 
highest  numbers  of  these  cells  have  been  found  in  pemphigus  (4,800), 
it  has  been  shown  by  Canon  and  verified  by  Zappert  that  the  eosins 
are  affected  not  so  much  by  special  forms  of  cutaneous  lesions  as  by 
the  extent,  intensity,  and  lack  of  healing  tendency,  on  the  part  of  the 
lesion.  Moreover  it  appears  that  local  afflux  of  eosinophile  cells  oc- 
curs in  the  early  and  in  the  less  active  stages  of  many  cutaneous 
lesions,  and  is  often  insufficient  to  cause  a  general  increase  in  the 
blood.  That  many  lesions  are  caused  by  local  toxic  agents  having 
special  chemotactic  influence  over  eosinophile  cells  is  indicated  by  the 
fact  that  in  pemphigus  artificial  blisters  do  not  necessarily  contain  the 
larger  numbers  of  eosins  that  are  found  in  the  spontaneous  lesions. 
(Kreibich.) 

Among  the  diseases  showing  high  eosinophilia  may  be  mentioned  : 
pemphigus,  eczema,  scleroderma,  psoriasis,  pellagra,  lupus,  if  widespread, 
urticaria  (60  percent  Lazarus).  (Zappert,  Neusser,  Canon,  Tscheleneff", 
Laredde.) 

In  the  blood  of  leprosy,  Gaucher  and  Bensaude  found  8.48—28  per- 
cent, Darier  as  high  as  61  percent,  and  Bettman  7-18.4  percent. 

While  the  vesicles  of  herpes  zoster  may  contain  a  high  proportion  of 
eosins,  the  blood  usually  shows  no  increase  of  these  cells.     (Bettman.) 

Post-febrile  Eosinophilia. — In  nearly  all  forms  of  acute  polynuclear 
leucocytosis  an  absence  of  eosinophile  cells  has  been  noted.  Scarlet 
fever,  acute  rheumatism,  and  malaria,  sometimes  furnish  notable  ex- 
ceptions to  this  rule.  Early  in  the  decline  of  the  febrile  process,  and 
before  the  neutrophile  leucocytes  have  greatly  decreased,  eosinophile 
cells  begin  to  reappear,  and  may  shortly  be  found  in  more  than  normal 
numbers.  The  reappearance  of  eosinophile  cells  in  pneumonia  and 
septic  processes,  etc.,  has  often  been  found  to  herald  a  favorable  turn 
in  the  disease,  but  usually  other  favorable  clinical  symptoms  are  present 
at  the  same  time. 

In  malaria,  eosinophile  cells  usually  persist  in  small  numbers  during 
the  paroxysm,  while  in  the  afebrile  interval,  and  in  chronic  cases,  a 
slight  eosinophilia  exists  and  may  be  a  useful  diagnostic  feature  of  the 
blood. 

In  acute  rheumatism,  the  eosins  are  usually  present  in  moderate  num- 
bers during  the  fever,  increase  slightly  during  convalescence,  and  in 
one  of  Zappert's  cases  a  relapse  was  attended  with  a  further  increase. 

Acute  Exanthemata. — In  scarlatina  there  is  a  remarkable  exception 
to  the  usual  rule  that  eosins  disappear  during  febrile  leucocytoses,  for 
in  this  disease  the  eosinophile  cells  usually  persist  and  may  be  markedly 
increased.  This  peculiarity  was  first  noted  by  Kotschetkoif,  who 
found  that  the  oxyphile  cells  steadily  increase  during  the  fever,  reach 
a  maximum  in  the  second  or  third  weeks  (8-15  percent)  and  fall  to 
normal  in  six  weeks.  In  his  very  severe  cases  however  they  fell  more 
rapidly.  Rille  found  marked  eosinophilia  in  severe  cases  and  Zappert, 
Silvester,  and  Felsenthal,  have  added  confirmatory  reports. 


140  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

In  measles  the  eosins  are  usually  normal  or  diminished.  (Zappert, 
Felsenthal,  Cabot.) 

In  some  other  acute  simple  erythemata  Zappert  found  distinct  eosin- 
ophilia. 

Gonorrhea. — According  to  Bettman  eosins  appear  in  gonorrheal  pus 
during  the  first  few  days  of  the  disease  when  the  exudate  is  largely 
serous.  Here  as  elsewhere  it  seems  that  when  the  stage  of  exudation 
of  neutrophile  cells  is  reached  the  eosins  largely  or  entirely  disappear, 
to  return  again  during  the  decline  of  the  discharge.  This  latest  con- 
tributor also  agrees  that  the  involvement  of  the  posterior  urethra  and 
prostate  is  usually  attended  with  a  marked  increase  of  oxyphile  cells  in 
the  discharge,  and  he  finds  further  a  similar  influence  from  the  involve- 
ment of  the  epididymis. 

Most  observers  are  agreed  that  the  eosinophile  cells  of  the  blood  are 
increased  when  they  are  abundant  in  the  discharge,  but  not  in  any  pro- 
portionate degree.  (Posner,  Finger,  Pezzoli,  Janowski,  Epstein,  Tsche- 
leneff,  Vorbach.)  Bettman  found  25  percent  in  a  case  complicated  by 
epididymitis. 

Sypliilis. — A  very  uniform  increase  of  eosins  accompanying  cuta- 
neous syphilis  was  noted  by  Rille  and  by  Loos,  but  the  observations 
of  Muller  and  Rieder  and  of  Zappert,  though  less  numerous,  did  not 
bear  out  these  claims.  In  a  case  of  congenital  syphilis  Muller  and 
Rieder  found  a  well-marked  increase  (12  percent). 

Of  osteomalacia  Neusser  finds  two  types,  with,  and  without,  eosino- 
philia.  The  latter  are  usually  advanced  cases  with  inflammatory 
changes  in  the  bones  and  marrow  and  myelocytes  in  the  blood.  The 
former  include  those  cases  in  which  castration  has  been  followed  by  re- 
covery. 

Gout. — Neusser  first  called  attention  to  the  high  proportion  of 
eosinophile  cells  in  the  blood  of  gouty  subjects.  Although  his  opinion 
was  not  based  on  extensive  observations  or  reports,  it  will  generally  be 
found  that  in  the  gouty  diathesis  the  eosins  reach  Zappert's  intermediate 
or  high  normal  limits.  Yet  in  testing  this  rule  the  writer  soon  found 
that  this  feature  of  the  blood  is  of  little  value  in  the  diagnosis  of  acute 
gout,  meeting  with  cases  in  which  the  blood  contained  few  oxyphile 
cells.  In  the  irregular  manifestations  of  the  diathesis,  eosinophilia  ap- 
pears to  be  more  uniform  but  still  subject  to  many  variations. 

Intestinal  Parasites. — Infection  with  various  common  intestinal  para- 
sites is  accompanied  by  extreme  eosinophilia,  as  first  noted  by  Buckler 
in  1894. 

In  cases  infected  by  Oxyuris,  Buckler  found  1 9  percent  of  eosins ; 
by  Asearis,  16  percent;  Anchylostoma,  72  percent;  Tenia  mediocanel- 
lata,  34  percent.  In  most  of  these  cases  eosinophile  cells  and  Charcot- 
Leyden  crystals  are  abundant  in  the  feces. 

Anchylostomiasis,  however,  is  not  always  accompanied  by  eosino- 
philia or  crystals  in  feces.  (Ehrlich.)  In  the  anemia  from  Bothrioceph- 
alus  latus  Schumann  found  few  eosins  in  the  blood.  Trichinosis  has 
lately  been  added  to  the  list  of  diseases  marked  by  extreme  eosinophilia. 


ORIGIN  AND  SIGNIFICANCE  OF  EOSINOPHILIA.  141 

Origin  and  Significance  of  Eosinophilia. — The  very  diverse 
opinions  that  have  prevailed  regarding  the  origin  of  eosinophiha  can 
only  be  finally  reconciled  by  holding  strictly  to  the  view  that  eosino- 
phile  cells  are  derived  solely  from  the  eosinophile  cells  of  the  bone 
marrow.  That  a  local  multiplication  of  these  cells  may  occur  under 
many  circumstances  is  however  strongly  suggested  by  their  abundance 
in  certain  foci,  especially  in  the  skin  and  mucous  membranes.  Thus, 
in  the  absence  of  general  eosinophilia,  rich  deposits  of  eosinophile  cells 
are  often  found  in  normal  tissues,  in  cutaneous  vesicles  and  pustules, 
in  chronically  inflamed  mucous  membranes,  in  nasal  polyps  and  other 
tumors,  and  in  leprous,  tuberculous,  and  syphilitic  lesions.  Lately 
they  have  been  found  in  very  large  numbers  in  bloody  exudates  in 
the  pleura.  (Weiss.')  Their  abundance  in  the  mucosa  and  exudate 
of  the  inflamed  bronchi  in  asthma,  led  Neusser,  and  on  parallel  grounds 
many  others,  to  actively  maintain  their  local  origin  apart  from  the  bone 
marrow.  In  one  case  of  pemphigus  with  marked  local  and  general 
eosinophilia,  Neusser  *  is  reported  to  have  found  no  increase  of  eosins 
in  the  bone  marrow,  but  studies  in  this  important  field  are  yet  entirely 
inadequate  to  figure  in  the  discussion.  In  the  marrow  of  cases  of 
malaria  showing  eosinophilia  the  writer  found  an  increased  number  of 
eosinophile  cells,  while  in  other  cases  without  eosinophilia,  these  cells 
in  the  marrow  also  were  deficient.  Dominici  found  an  excess  of  eosins 
in  the  marrow  of  a  rabbit  showing  marked  eosinophilia. 

The  exponents  of  the  local  origin  of  eosinophile  cells  have  been  un- 
able to  bring  forward  evidence  to  prove  that  these  cells  undergo 
mitotic  division  in  the  skin  or  that  neutrophile  granules  are  there 
transformed  into  eosinophile. 

The  writer  believes  that  all  the  phenomena  connected  with  general 
and  local  eosinophilia  can  best  be  explained  by  the  same  chemotactic 
principles  that  are  known  to  control  neutrophile  cells.  From  the  ob- 
servations on  eosins  in  gonorrheal  pus,  in  cutaneous  and  serous  exu- 
dates, and  in  the  blood,  it  appears  that  inflammatory  products  attract 
eosins  at  one  stage  and  neutrophile  cells  at  another,  more  acute,  stage. 
As  purulent  exudates  of  small  extent  may  cause  no  general  leucocy- 
tosis  (e.  g.,  furunculosis),  so,  many  cutaneous  lesions  with  exudates 
composed  largely  of  eosins  cause  no  general  increase  in  the  circulation, 
but  when  either  reaches  a  certain  grade  the  neutrophile  or  eosinophile 
cells  are  drawn  from  the  marrow  in  sufficient  numbers  to  cause  a 
noticeable  increase  in  the  blood. 

Ehrlich  finds  reason  to  believe  that  substances  which  attract  eosino- 
phile cells  may  be  derived  from  the  destruction  of  epithelial  cells,  as  seen 
in  the  local  eosinophilia  about  the  ulcers  of  lupus  after  injection  of 
tuberculin;  from  the  mucin  in  nasal  polyps;  and  from  toxines  of  para- 
sites. Michaelis  has  shown  that  when  lactation  is  interrupted  in  the 
guinea-pig  many  eosinophile  cells  collect  in  the  breasts.  But  in  the 
human  breast  after  stagnation  of  milk  Unger  found  many  mast-cells. 

Weiss  has  recently  maintained  that  local  eosinophilia  tends  to  occur 
where  there  is  extensive  extravasation  of  blood,  the  derivatives  of  Hb 


142  THE  LEUCOCYTES  AND  LEUCOCYTOSIS.  ; 

being  absorbed  by  the  polynuclear  cells  and  deposited  in  the  form  of 
eosinophil  granules.  He  bases  this  opinion  on  the  observation  of  a 
case  of  septicemia  with  hemorrhagic  pleural  effusion.  In  the  blood 
there  were  40  percent  of  eosinophile  cells,  while  in  the  sediment  of  the 
exudate  76  percent  of  these  cells  were  found.  He  refers  to  two  other 
somewhat  similar  cases  reported  by  Harmser. 

The  most  comprehensive  view  of  the  significance  of  eosinophilia  is 
that  of  Neusser  ^  and  his  pupils,  who,  from  extensive  observations  have 
found  evidence  that  the  supphj  of  eosinophile  cells  in  the  blood  is  con- 
trolled by  the  sympathetic  nervous  system,  and  that  eosinophilia  is  the  ex- 
pression of  sym,pathetic  nervous  irritation.  This  irritation  they  believe 
may  proceed  from  the  generative  organs,  ovaries,  uterus,  or  prostate, 
disorders  of  which,  with  their  related  neuroses,  are  usually  accom- 
panied by  eosinophilia  ;  from  the  skin,  diseases  of  which  have  furnished 
some  of  the  best  examples  of  eosinophilia ;  from  the  intestines,  from 
which  the  toxemia  of  parasites  and  that  of  gout,  which  Neusser  regards 
as  of  intestinal  autotoxic  origin,  give  rise  to  marked  eosinophilia,  etc. 

Following  out  this  idea  Neusser  has  elaborated  an  extensive  scheme 
of  the  altruistic  relations  of  the  viscera  in  disease,  by  which  he  is  able 
to  correlate  nearly  all  the  diseases  showing  eosinophilia.  He  finds  a 
necessary  sequence  of  events  in  a  case  which  suffered  from  migraine  in 
youth,  pemphigus  and  asthma  in  old  age,  and  died  from  cancer  of  the 
prostate  with  general  metastasis  in  the  bone  marrow. 

Although  the  recent  tendency  has  been  to  deny  any  great  impor- 
tance in  Neusser's  conception  of  eosinophilia,  it  must  be  remembered 
that  it  is  based  on  a  well-known  and  far-reaching  principle  in  path- 
ology. While  in  practice  a  great  many  exceptions  have  been  found 
to  the  rules  which  he  formulated,  it  will  yet  be  wise  to  keep  them  in 
mind  in  drawing  conclusions  from  eosinophilia. 

Value  of  EosinopMlia  in  Diagnosis. — In  general,  the  presence  of  a 
moderate  or  increased  number  of  eosins  in  the  blood  is  often  of  value 
in  the  diagnosis  between  a  condition  in  which  these  cells  are  known  to 
persist  as  against  those  in  which  they  are  commonly  absent.  The 
writer  has  found  situations  of  the  sort  most  frequently  in  the  diagnosis 
between  gouty  and  tuberculous  affections. 

Other  situations  have  arisen  in  the  diagnosis  between  active  malarial 
and  typhoid  fevers,  scarlet  fever  and  measles,  trichinosis  and  rheuma- 
tism. 

In  prognosis  the  reappearance  of  eosins  in  suppurative  processes  is 
undoubtedly  a  fav^orable  sign  indicating  the  approach  of  defervescence. 

Many  clever  deductions  have  been  drawn  by  Neusser  and  his  pupils 
from  the  behavior  of  eosinophile  cells  in  the  blood,  but  others  have  not 
been  so  successful  in  this  field. 

OCCURRENCE    OF    MAST-CELLS. 

The  knowledge  of  mast-cells  dates  chiefly  from  the  studies  of  West- 
phal,  1880,  and  of  Unna,  who  found  abundant  collections  of  large 


OCCURRENCE  OF  MYELOCYTES.  143 

mononuclear  cells  with  large  strongly  basophile  granules,  in  tumors,  and 
in  tuberculous,  syphilitic,  and  other  lesions  of  the  skin.  The  occurrence 
of  such  cells  in  tissues  has  since  been  described  by  many  writers  and 
it  is  now  accepted  that  their  appearance  is  favored  by  a  considerable  va- 
riety of  chronic  disturbances  of  nutrition  in  tissues  and  that  they  are 
commonly  associated  with  eosinophile  cells.  The  majority  of  coarsely 
granular  basophilic  cells  in  tissues,  are  not,  however,  identical  with  the 
mast-cells  of  the  blood. 

In  the  blood,  Canon  failed  to  find  them  in  9  of  22  healthy  subjects, 
counting  500-1,000  leucocytes,  while  in  the  other  13  cases  they 
yielded  an  average  of  .47  percent.  In  a  variety  of  skin  diseases  (20 
cases)  they  were  slightly  more  numerous  (.58  percent)  and  in  general 
were  slightly  increased  when  eosinophile  cells  were  abundant.  Sher- 
rington found  them  distinctlv  increased  in  the  blood  of  moribund 
cholera  patients.  The  writer  constantly  fails  to  find  mast-cells  in  the 
better  class  of  healthy  subjects,  but  in  hospital  and  dispensary  cases 
with  lesser  ailments  they  appear  to  be  more  numerous.  In  cases  of 
severe  malaria  he  has  seen  them  more  abundant  in  the  blood  than  in 
any  condition  except  leukemia,  while  in  the  viscera  of  such  cases  large 
granular  basophilic  cells  were  unusually  frequent. 

Neusser  examined  a  gonorrheal  exudate  composed  exclusively  of 
mast-cells.     {^Letter  to  Ehrlk-h,  Die  Anaemie,  I.,  p.  111.) 

In  myelogenous  leukemia  there  is,  in  the  majority  of  cases,  mast-cell 
leucocytosis,  these  cells  being  here  more  abundant  than  in  any  other 
condition.  They  often  outnumber  the  eosinophile  cells  (Ehrlich),  and 
must  be  considered  the  sole  isolated  pathognomonic  sign  of  this  disease. 
The  writer  cannot  support  Ehrlich's  statement  (D/e  Anaemie,  p.  123), 
that  they  are  invariably  present  in  considerable  numbers  in  myeloge- 
nous leukemia,  having  missed  them  entirely  in  some  cases  of  acute 
leukemia  and  searched  in  vain  over  thousands  of  cells  in  chronic  cases. 

Ehrlich  believes  that  mast-cells  are  derived  exclusively  from  the 
bone  marrow,  and  respond  to  chemotactic  influence  from  principles 
however  which  are  very  rarely  present  in  the  human  organism. 

OCCURRENCE    OF   MYELOCYTES  (EHRLICH'S). 

Although  the  eosinophile  myelocytes  and  to  a  less  extent  CorniPs 
very  large  pale  neutrophile  myelocytes  are  found  almost  exclusively 
in  myelogenous  leukemia,  the  smaller  variety  of  mononuclear  neutro- 
phile cells  have  been  shown  to  occur  in  the  blood  in  a  considerable 
variety  of  conditions. 

From  the  many  recent  reports  of  the  occurrence  of  a  few  myelocytes 
in  the  blood  it  appears  that  such  cells  may  be  swept  from  the  marrow 
by  several  distinct  causes. 

1.  Accompanying  the  polynuclear  leucocytosis  of  infec- 
tious DISEASES,  a  considerable  number  of  myelocytes  may  be  found. 
This  fact  first  appeared  in  the  studies  of  Turk,  was  emphasized  through 
the  discovery  by  Engel  of  unusually  large  numbers  (12  percent)  in 


144  THE  LEUCOCYTES  AND  LEUCOCYTOSIS.  ; 

unfavorable  cases  of  diphtheria,  and  has  since  been  extended  by  others 
to  most  severe,  acute,  and  subacute  infections. 

Usually  the  percentage  of  these  cells  in  polynuclear  leucocytosis  is 
much  lower  than  in  diphtheria,  and  not  being  associated  with  eosino- 
phile  cells  or  mast-cells  it  can  seldom  raise  a  suspicion  of  leukemia. 
Nevertheless  a  difficulty  arose  with  a  case  of  acute  leukemia,  observed 
by  Thomson  and  the  writer,  in  which  the  first  examination  of  the 
blood  in  a  case  resembling  typhoid  fever  showed  leucocytosis  and  5 
percent  of  myelocytes.  A  few  days  later  there  were  12  percent  of 
myelocytes  and  at  the  autopsy  the  lesions  of  leukemia  were  demon- 
strated.    Eosins  and  mast-cells  were  absent. 

The  presence  of  myelocytes  in  polynuclear  leucocytosis  is  readily  ex- 
plained by  the  hyperplasia  and  hyperemia  of  the  marrow. 

2.  In  primary  and  secondary  anemias  of  severe,  or  even  of 
moderate  grade,  a  few  myelocytes  have  frequently  been  observed. 
(Klein,  Krebs,  Loos,  Hammerschlag,  Capps.)  They  are  perhaps  most 
frequently  seen  in  pernicious  anemia  (Neusser),  in  the  anemia  of 
syphilis  (Rille),  with  malignant  tumors  (Cabot),  and  in  v.  Jaksch's 
anemia.  It  has  been  supposed  that  tumors  involving  the  marrow 
would  yield  myelocytes  as  well  as  eosins  in  the  blood,  but  this  suppo- 
sition has  not  been  verified  in  fact,  although  they  have  been  noted  in 
considerable  numbers  in  rachitis,  osteomyelitis,  and  osteomalacia. 

In  all  the  above  conditions  the  appearance  of  myelocytes  must  be 
referred  to  hyperplasia  of  red  marrow,  or  mechanical  dislodgment  of 
marrow  cells  resulting  from  structural  changes  in  the  marrow  or 
hydremic  states  of  the  blood  plasma. 

3.  After  severe  mechanical  disturbances  of  the  circu- 
lation a  few  myelocytes  may  be  found  in  the  blood.  This  rule  is 
illustrated  by  their  discovery  in  the  blood  of  uremia,  asphyxia,  acute 
mania,  etc.  (Neusser.)  The  writer  has  seen  a  few  myelocytes  appear 
during  ante-mortem  leucocytosis. 

The  occurrence  of  myelocytes  in  leukemia  will  be  considered  with 
that  disease. 

LYMPHOCYTOSIS. 

A  relative  or  absolute  increase  of  lymphocytes  in  the  blood  is  of 
frequent  occurrence  and  has  at  times  important  significance.  In 
speaking  of  lymphocytosis,  as  of  eosinophilia,  since  each  of  the  cells 
concerned  represents  an  independent  series,  conceptions  will  be  more 
accurate  if  the  actual  numbers  found,  as  well  as  the  relative  propor- 
tions, are  reported.  In  estimating  lymphocytosis  it  is  important  to 
distinguish  also  between  the  large  lymphocytes  and  large  mononuclear 
leucocytes  with  faintly  basophile  protoplasm. 

Physiological  variations  in  the  proportions  of  lymphocytes  are 
observed  at  different  periods  of  life.  The  first  embryonal  leucocytes 
are  all  mononuclear  basophile  cells  (Saxer),  but  as  other  varieties  of 
leucocytes  make  their  appearance,  the  proportion  of  lymphocytes 
diminishes  till,  at  birth,  the  healthy  infant  shows  50-66  percent  of 


LYMPHOCYTOSIS.  145 

these  cells.  Throuj^hout  healtliy  iafancy,  this  proportion  steadily 
diminishes  till,  at  the  tenth  to  fourteenth  years,  the  usual  percentage 
is  27-30  percent. 

Pathological  Lymphocytosis, — Anything  which  interferes  with 
the  natural  development  of  the  infant  retards  tiie  progress  of  this 
change  in  the  proportion  of  lymphocytes,  which  is  found  to  be  rela- 
tively high  in  anemic  or  poorly  developed  children.  Sometimes  the 
development  of  lymphatic  tissue  reaches  an  excessive  grade,  and  a 
condition  known  as  ^' eonsfitutio  li/mpJiatica'^  is  established,  marked  by 
lymphocytosis,  with  simple  hyperplasia  of  many  lymph  nodes  and  of 
the  red  marrow,  by  rachitis,  and  by  many  other  developmental  anom- 
alies. Since  Ohlmacher  has  demonstrated  that  most  cases  of  idio- 
pathic  epilepsy  are  associated  with  the  coiistitutio  li/mphatica,  it  is 
reasonable  to  suppose  that  lymphocytosis  is  a  frequent  feature  of  the 
blood  in  such  cases.  The  lymphocytosis  of  Basedoiv's  disease  should 
probably  be  placed  in  this  connection. 

Rachitis  is  almost  always  attended  with  a  well-marked  increase  in 
the  number  and  proportion  of  lymphocytes  in  the  blood.  (Rieder, 
Monti,  Berggrun.)  This  fact  is  plainly  referable  to  the  lymphoid 
hyperplasia  and  the  hyperemia  of  the  bone  marrow  in  this  disease. 

In  some  tumors  Reinbach  has  reported  an  extreme  diminution  of 
lymphocytes,  only  .6  percent  being  present  in  one  case  of  Ii/mpho-sar- 
coma  colli.  This  result  is  referred  by  Ehrlich  to  closure  of  the  lymph 
paths  by  sarcomatous  growth.  In  many  lymphomata,  however,  there 
is  marked  uniform  lymphocytosis,  and  it  would  appear  that  these  neo- 
plasms when  leaving  the  lymph  paths  free  induce  lymphocytosis.  As 
the  more  malignant  tumors  obliterate  lymph  paths,  some  inference  re- 
garding prognosis  may  be  derived  from  the  presence  or  absence  of 
lymphocytosis  in  these  cases.  Various  other  types  of  sarcoma  are  fre- 
quently associated  with  lymphocytosis  and  there  are  on  record  several 
cases  of  sarcoma  associated  with  lymphatic  leukemia.  (See  Leukemia.) 
In  most  splenic  tumors  there  is  relative  or  absolute  lymphocytosis. 
(Muller  and  Rieder,  Weiss.* )  On  the  other  hand,  after  splenectomy 
in  animals,  prolonged  lymphocytosis  is  usnally  observed.  (Kurloff.) 
In  man,  both  mononuclear  and  polynuclear  cells  are  usually  much  in- 
creased after  this  operation. 

The  lymphocytosis  of  infectious  di.seases  is  probably  always  associated 
with  acute  hyperplasia  of  the  lymphatic  structures. 

In  typhoid  fever  the  hyperplasia  is  most  marked  in  the  abdominal 
nodes  and  spleen,  but  may  become  more  general.  There  is  in  this 
disease  a  relative  lymphocytosis,  which  after  the  first  week  usually  in- 
creases till  there  is  a  high  percentage  of  lymphocytes.  The  writer  has 
found  a  uniform  relation  between  the  lymphocytes  in  the  blood  and 
the  grade  of  lymphatic  hyperplasia  found  at  autopsy.  In  one  case  the 
examination  of  the  blood  led  to  a  strong  suspicion  of  lymphatic  leuke- 
mia, and  at  autopsy  the  mesenteric  glands  were  of  unusually  large  size, 
and  the  edges  of  the  partly  necrotic  intestinal  ulcers  rose  1.5  cm.  above 
the  mucosa. 
10 


146  THE  LEUCOCYTES  AND  LEUCOCYTOSIS. 

In  the  infectious  diseases  of  children  a  well-marked  lymphocytosis, 
together  with  increase  of  neutrophile  cells,  is  so  common  that  it  should 
occasion  no  surprise,  and  points  merely  to  a  special  involvement  of  the 
lymphoid  tissues. 

In  diphtheria  a  close  relation  between  lymphocytosis  and  lymphatic 
hyperplasia  was  noted  in  some  of  the  writer's  cases.  In  others,  how- 
ever, the  lymphocytes,  though  increased,  were  not  in  relatively  high 
proportion,  while  the  cervical  lymph  nodes  were  much  enlarged. 

In  broncho-pneumonia  Cabot  reports  a  case  with  94,600  leucocytes, 
69  percent  of  which  were  lymphocytes. 

In  whooping-cough  during  the  convulsive  period  Meunier  found  the 
neutrophile  cells  doubled  but  the  lymphocytes  quadrupled  in  number. 

During  the  course  of  measles,  at  the  close  of  scarlet  fever  or  small- 
pox, and  during  prolonged  lysis  in  pneumonia  (Klein),  a  relatively 
high  proportion  or  increased  number  of  lymphocytes  is  usually  ob- 
served. 

In  the  less  acute  diarrheas  of  infancy,  lymphocytosis  is  the  rule, 
and  is  referable  to  the  hyperplasia  and  irritation  of  the  intestinal  lym- 
phoid structures.  (Weiss.")  Digestion  Icucocj/tosis  is  also  for  the  same 
reason  largely  a  lymphocytosis.  (Kieder.)  In  the  initial  or  persistent 
hypoleucocytosis  sometimes  observed  in  infectious  diseases  (pneumonia, 
diphtheria),  the  remaining  cells  arc  largely  lymphocytes. 

Of  chronic  diseases  affecting  the  lym})hatic  tissues  both  tuberculosis 
and  syphilis  are  frequent  causes  of  lymphocytosis. 

In  various  forms  of  pulmonary  and  visceral  tubereidosis  the  leuco- 
cytes are  usually  normal  or  diminished  in  number  and  the  majority  of 
those  remaining  are  lymphocytes,  a  relation  which  is  of  course  altered 
when  from  any  cause  polynuclear  leucocytosis  is  established.  The 
condition  of  the  blood  is  here  in  accord  witli  tlie  histological  character 
of  the  visceral  lesions  in  which  the  infiltration  with  "  round  cells  "  is 
a  prominent  feature. 

Lymphatic  anemia  is  a  term  applied  by  Xeusser  to  a  rather  charac- 
teristic group  of  cases  in  which  there  is  chlorotic  anemia,  lymphocy- 
tosis, and,  usually,  evidence  of  tuberculosis.  Kieder  could  not  agree 
with  Neusser  that  most  cases  of  chlorotic  anemia  with  increase  of 
lymphocytes  are  associated  with  tuberculosis  and  are  of  less  favorable 
prognosis.  The  writer  finds  that  the  chlorotic  anemia  of  tuberculosis 
as  a  rule  shows  absence  of  eosins  as  well  as  increase  of  lymphocytes. 

Injections  of  tuberculin  are  usually  followed  by  fever  and  lymphocy- 
tosis, which  may  be  referred  to  irritation  of  inflamed  tuberculous 
lymph  nodes.     (Ehrlich.) 

In  congenital  and  in  secondfiry  acquired  syphilis,  it  has  been  shown 
by  Bieganski,  Rille,  Anc,  and  others,  that  there  is  uniform  and  con- 
siderable lymphocytosis,  which  must  here  again  be  referred  to  the  in- 
volvement of  lymph  nodes. 

The  presence  of  an  increased  proportion  of  lymphocytes  in  some 
cases  of  scurvy  and  hemophilia,  has  been  observed  by  Neusser,  and  the 
same  feature  is  recognized  by  Ehrlich  in  many  seve7'e  anemias.     In 


* 


LARGE  MONONUCLEAR  LEUCOCYTES  IN  LYMPHOCYTOSIS.   147 

anemia  infantum  pseudo-leukemica  the  very  numerous  leucocytes  are 
principally  large  mononuclear  cells.  In  pernicious  anemia,  a  consider- 
able leucocytosis  may  consist  largely  of  lymphocytes. 

ExPERiMEXTAL  LYMPHOCYTOSIS  has  been  produced  by  injection  of 
tuberculin  and  of  extract  of  carcinomatous  tumors  by  Grawitz  who 
refers  this  eifect  to  the  lymphogogic  action  of  these  agents.  Wald- 
stein  reports  lymphocytosis  in  rabbits  from  pilocarpine,  which  the 
writer  finds  to  induce  in  rabbits  only  a  relative  increase  of  lympho- 
cytes by  diminution  of  polynuclear  cells. 

In  the  origin  of  lymphocytosis  Ehrlich  finds  that  mechanical  rather 
than  chemotactic  influences  are  chiefly  or  wholly  concerned,  since  the 
lymphocytes  are  not  sensible  to  chemotactic  attraction. 

The  histology  of  tuberculous  and  syphilitic  lesions,  especially  of 
the  "  lymphoid  tubercle  "  and  chancre,  indicate  that  there  are  some 
conditions  which  gather  large  numbers  of  these  cells  from  the  blood 
and  lymph  nodes.  Janowsky's  experiments  in  which  large  collections 
of  lymphoid  cells  were  shown  to  gather  at  the  site  of  injection  of 
turpentine,  etc.,  point  to  the  same  conclusion.  In  all  of  these  situa- 
tions, however,  the  lymjjhocytes,  like  eosinophile  cells,  seem  to  follow 
entirely  different  rules  from  those  governing  neutrophile  cells,  a  fact 
which  emphasizes  the  importance  of  Kanthack's  classification  of  lym- 
phocytes and  eosins  as  celomic,  the  neutrophile,  as  hemic  cells. 

In  general,  lymphocytosis  seems  to  result  from  mechanical  discharge  of 
cells  from  lymphoid  structures,  aided  by  diminished  blood  pressure  and 
increased  flow  of  lymph. 

Relation  of  Lymphocytosis  and  Eosinophilia. — It  is  of  interest  to 
note  that  a  peculiar  relation  seems  to  exist  between  the  appearance  in 
blood  and  tissues  of  lymphocytes  and  eosinophile  cells.  Neither  are 
apt  to  appear  when  neutrophile  cells  are  prevailing  in  blood  or  exu- 
date, but  either  may  be  found  in  the  less  acute  exudative  processes. 
The  sequence  of  lymphocytosis  followed  by  eosinophilia  is  especially 
clear  after  the  injection  of  tuberculin  (Grawitz)  and  after  splenectomy 
in  animals.  (Kurloff.)  Many  other  less  patent  examples  of  this  rela- 
tion may  be  noted  by  comparing  the  conditions  showing  lymphocytosis 
or  eosinophilia,  as  above  detailed. 

Large  Mononuclear  Leucocytes  in  Lymphocytosis. — In  the  ma- 
jority of  cases  reported  as  showing  lymphocytosis  no  distinction  has 
been  made  between  lymphocytes  and  large  mononuclear  leucocytes. 
Yet  there  is  considerable  evidence  to  show,  as  Ehrlich  believes,  that 
these  cells  represent  separate  series,  and  in  some  conditions  it  is  the 
large  mononuclear  leucocytes  and  not  the  lymphocytes  which  are  in- 
creased in  number.  This  fact  has  been  noted  in  v.  JaJcsch's  anemia, 
especially  by  Hock  and  Schlesinger ;  in  rachitis  by  Kieder ;  in  syphilis 
by  Rille  ;  and  after  smallpox  and  scarlet  fever,  by  Felsenthal.^  It  is 
sometimes  distinctly  seen  after  splenectomy.  In  the  cases  of  acute 
lymphemia  described  by  Frankel  and  others,  the  majority  of  cells  are 
of  large  size.  The  significance  of  an  increase  of  large  mononuclear 
cells  apart  from  lymphocytes  cannot  at  present  be  stated. 


148  THE  LEUCOCYTES  AND  LEUCOYCTOSIS. 

Bibliography. 

EosiNOPHiLiA,  Lymphocytosis,  etc. 

Anc.     Diss.  Wratsch.,  1895,  No.  5. 
Aronson,  Phillip.     Deut.  med.  Woch.,  1892,  No.  3. 
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Canon.     Deut.  med.  Woch.,  1892,  p.  206. 

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Castellino.     Gaz.  d.  ospedali,  1891,  p.  476. 

Darier.     Annal.  de  Dermat.,  1896,  p.  842. 

Dominici.     Compt.  Rend.  Soc.  Biol.,  1900,  p.  73. 

Engel.     Deut.  med.  Woch.,  1899,  pp.  118,  137. 

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Ewing.     N.  Y.  Med.  Jour.,  Vol.  ('>6,  p.  37. 

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Krypiakiewicz.     Wien.  med.  AVoch.,  1892,  No.  25. 

Kurloff.     Abstract  bv  P^hrlich,  Die  Anaemic,  I. 

Laredde.     Annal.  de  Dermat.,  18i)8,  p.  1016. 

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Fig.  19. 


CHAPTER    V. 
DEVELOPMENT   OF   BLOOD  CELLS. 

AVhile  the  mode  of  origin  of  the  first  blood  cells  of  the  embryo  has 
been  fully  determined,  the  alterations  in  the  process  which  supervene 
durins:  late  fetal  and  adult  life  still  remain  an  obscure  and  difficult 
problem.  It  becomes  necessary,  therefore,  to  consider  separately  the 
formation  of  blood  cells  at  different  periods  of  intra-  and  extra-uterine 
life. 

ERYTHROCYTES. 

Formation  of  Red  Cells  in  the  Embryo. — In  early  embryonal 
life  the  formation  of  red  cells  in  isolated  groups  of  mesodermal  cells  in 
the  "vascular  area  "  of  the  chick  was  first  noted  by  Pander,  who  named 
these  foci  "  blood  islands."  The 
process  was  later  studied  more 
closely  by  Hiss,  Remak,  Kolliker,^ 
"VVissosky,  Klein,  Strieker,  and 
others.  From  their  researches  it 
appears  that  the  first  blood  cells  of 
vertebrates  are  formed  by  the  ap- 
pearance of  Hb  in  some  of  the  cells 
of  the  mesodermal  cords  which  go 
to  form  the  first  capillaries.  Upon 
the  formation  of  the  vessel  these 
cells  lie  free  in  the  lumen  as  nu- 
cleated red  blood  cells.  Both  the 
vessel  wall  and  the  primitive  ery- 
throcytes are  thus  derived  from  the 
same  group  of  cells. 

Theory  of  Endoglobular  Formation 
of  Red  Cells. — In  many  mammals 
all  the  early  red  cells  are  nu- 
cleated, but  in  some  (rat,  guinea- 
pig),  many  non-nucleated  red  cells 
are  abundant  at  an  early  stage,  al- 
though in  the  human  embryo  they  appear  certainly  only  after  the  fourth 
week  and  form  only  25  percent  of  the  red  cells  at  the  fourth  month. 
The  formation  of  the  first  non-nucleated  red  cells  has  been  studied  by 
Schafer,  Ranvier,  Hayem,  and  others,  who  describe  in  the  rat  and 
guinea-pig,  the  appearance  in  certain  large  connective  tissue  cells 
(angioblasts,  hematoblasts,  cellules  vaso-formatives)  of  discs  and  globules 


Theory  of  eudoglobiilai-  foriuatiou  of  red  cells 

(SCHAFEK.) 


150  DEVELOPMENT  OF  BLOOD   CELLS. 

of  hemoglobin,  which,  by  subdivision  of  the  body  of  the  cell,  become 
non-nucleated  red  blood  cells.  These  red  cells  soon  come  to  lie  free 
in  a  central  cavity  within  the  cell,  which  is  itself  transformed  into  a 
young  capillary.  According  to  this  theory,  the  red  discs  are  not  cells 
but  fragments  of  cells,  of  endoglobular  origin,  ichile  nucleated  red  cells  have 
a  different  signifiGance,  being  formed  by  mitotic  division  of  other  nucleated 
red  cells.  With  the  development  of  the  lymphatic  system  and  liver, 
the  intracellular  formation  of  red  cells  is  said  to  cease,  and  few  or  no 
traces  of  it  have  been  described  in  most  mammals  at  birth.  Kuborn 
and  Malassez,  however,  describe  the  formation  of  red  cells  in  the  late 
embryonal  liver  and  marrow,  through  gemmation  of  the  giant  cells  of 
these  organs. 

The  theory  of  intracellular  formation  of  blood  discs  has  not  been  supported 
by  more  recent  investigations.  Spuler  and  Saxer  find  no  traces  of  such  a 
process,  regarding  the  vaso-formative  cells  of  Ranvier  as  endothelial  cells 
which  have  become  separated  from  the  delicate  young  vessels  and  have 
carried  with  them  some  of  the  red  cells  of  the  vessel.  In  the  adult  marrow 
such  cells  have  not  been  fully  identified.  Recently,  however,  Francois  has 
attempted  to  substantiate  the  theory  of  endogenous  red  cell  formation  in 
the  rabbit. 

In  later  embryonal  periods  the  process  of  development  of  red  cells  is 
very  similar  to  that  in  extra-uterine  life. 

Mode  of  Origin  of  Red  Cells  in  Late  Embryonal  and  Extra-uterine  Life. 
— That  the  nucleated  red  cells  of  the  nutrrow  multiply  by  indirect  di- 
vision of  other  nucleated  red  cells  was  first  stated  by  liizzozero,'  and 
has  been  accepted  by  most  histologists.  Bizzozero,  however,  claimed 
that  the  large  nucleated  red  cell  of  the  adult  marrow  is  the  most 
primitive  cell  in  the  body  capable  of  producing  erythrocytes,  believing 
that  the  intermediate  stages  between  the  embryonal  wandering  cell  and 
the  colored  erythroblast  have  been  lost  in  later  embryonal  life.  But 
it  has  since  been  shown  to  the  satisfaction  of  most  authorities,  that  the 
series  of  mitoses  leading  to  the  production  of- red  discs  begins  in  color- 
less cells  antecedent  to  the  large  nucleated  red  cells,  and  which  are  only 
very  slightly  different  from  the  original  mesoblastic  cell  of  the  embryo. 
It  thus  appears  that  the  formation  of  nucleated  red  cells  in  the  adult  is 
practically  the  same  as  in  the  embryo  and  that  at  all  periods  of  life  the 
red  cell  is  the  product  of  several  series  of  mitoses  of  a  colorless  meso- 
blastic cell.  The  difficulty  of  tracing  this  series  from  the  large  nu- 
cleated red  cell  to  the  colorless  mesoblastic  "  mother  cell "  in  the  mar- 
row, has  given  rise  to  the  diverse  opinions  now  held  regarding  the 
ultimate  development  of  red  corpuscles. 

As  to  the  exact  morphology  of  the  original  erythroblasts  of  adult  mar- 
row, opinions  are  more  or  less  at  variance,  l)ut  it  is  agreed  by  Neumann,^ 
RindHeisch,  Obrastzow,'  Malassez,  Howell,  Lowit,^  Muller,  and  many 
others,  that  it  is  a  large  mononuclear  cell,  larger  than  the  ordinary 
nucleated  red  cell,  with  pale  nucleus  and  without  hemoglobin,  and  it 
is  usually  described  as  lacking  a  nucleolus.  From  these  "  embryonal  " 
cells  are  derived,  by  mitotic  division,  two  or  more  series  of  cells  which 


ERYTHROCYTES.  151 

gradually  approach  the  type  of  the  nucleated  red  cell  which  is  rich  in 
hemoglobin,  and  whose  nucleus  is  compact  and  pyknomorphous. 

Among  dissenting  opinions  may  be  mentioned  the  conclusions  of  Foa, 
according  to  whom  the  red  cells  are  derived  from  the  giant  cells  of  the 
marrow,  spleen,  and  liver,  and  the  theory  of  Hayem,2  partially  accepted  by 
Afanissiew  and  Pouchet,  that  the  red  discs  are  derived  from  the  blood 
plates. 

Regarding  important  details  in  the  origin  and  relation  of  the  formative 
erytkroblasts,  opinions  are  also  widely  at  variance. 

Lowit  describes  in  the  marrow,  spleen  and  lymph  nodes,  two  separate 
series  of  colorless  cells  which  produce,  one,  leucocytes,  the  other,  red  cells. 
The  cells  of  these  two  series  differ  in  the  structure  of  the  nucleus,  in  the 
fact  that  one  type  (leucoblasts)  exhibits  ameboid  and  phagocytic  activity, 
and  in  their  method  of  division,  the  erythroblasts  multiplying  by  indirect 
division,  the  leucoblasts  by  a  modified  form  of  karyokinesis  described  as 
divisio  indirecfa  per  granula.  According  to  Lowit  the  red  cells  are  derived 
from  the  erythroblasts  after  these  have  reached  the  circulation  from  the 
lymphoid  tissues. 

Bizzozero  2  describes  the  primitive  erythroblast  as  separate  from  the 
leucoblast,  both  in  morphology  and  especially  in  its  relation  to  the  blood 
vessels  of  the  marrow.  While  numerous  nucleated  red  cells  in  mitotic 
division  are  found,  accoi'ding  to  Bizzozero,  in  the  masses  of  cells  lying  within 
the  capillaries  of  the  marrow  of  birds,  intervascular  tissue  is  entirely  free 
from  such  cells.  The  capillary  network  of  the  marrow  is,  therefore,  an  en- 
dovascular  blood-gland.  This  observation  has  been  verified  by  Torre, 
Salvioli,  and  Denys,  for  nucleated  hemoglobin-holding  cells,  but  other 
authors  trace  the  erythroblasts  back  to  colorless  cells,  which  are  not  in- 
variably intravascular.  In  man,  however,  while  the  erythroblasts  lie  closer 
to  the  lumen  of  the  capillary  than  do  the  leucoblasts,  the  walls  of  the 
sinuses  are  incomplete  and  the  islands  of  nucleated  red  cells  are  found  in  the 
midst  of  masses  of  leucoblasts.     (Muir.) 

H.  F.  Muller  describes  a  common  form  of  mother  cell,  for  both  red  and 
white  blood  cells.  By  their  indirect  division  are  produced  (1)  cells  which 
resemble  the  original,  (2)  mononuclear  leucocytes,  and  (3)  nucleated  cells 
which  develop  hemoglobin  and  by  the  gradual  disappearance  of  their  nuclei 
become  the  non-nucleated  red  blood  discs. 

Denys  believes,  with  Lowit,  that  there  are  two  separate  developmental 
series  of  leucoblasts  and  erythroblasts,  each  of  which  multiplies  by  mitosis, 
and  is  originally  coloi-less.  Both  are  ameboid,  but  the  erythroblasts  are 
very  slightly  so,  Denys,  like  Bizzozero,  finds  that  the  leucoblasts  lie  in  the 
cords  outside  the  vessels  of  the  marrow,  while  the  erythroblasts  are  found 
within  the  vessels. 

Hayem  believes  the  red  blood  discs  to  be  derived  from  the  blood  plates  of 
Bizzozero,  which  he  therefore  calls  ^'  hematoblasts.''^  He  claims  to  have  seen 
all  transition  forms  between  blood  plates  and  red  blood  cells  and  finds  that 
when  blood  formation  is  unusually  active  the  blood  plates  and  the  transition 
forms  are  more  abundant.  In  regard  to  many  details  of  the  origin  of  blood 
plates  and  their  transformation  into  red  cells,  Hayem  was  unable  to  reach 
satisfactory  conclusions. 

To  summarize  the  work  in  this  field,  it  may  be  said  that  we  do  not 
know  certainly  whether  any  common  cell  of  origin  of  red  and  white 
blood  corpuscles  exists  in  the  late  embryo  or  adult,  or  whether  these 
corpuscles  are  derived  from  completely  separate  series.     The  late  con- 


152  DEVELOPMENT  OF  BLOOD   CELLS. 

tributions  favor  the  existence  of  a  common  mother  cell  for  both  groups, 
persisting  at  least  into  late  embryonal  life. 

The  Transformation  of  Nucleated  Red  Cells  into  Blood  Discs. — To  that 
minority  of  observers  who  believe  that  the  red  blood  discs  are  derived 
from  other  sources  than  the  nucleated  red  cells  the  task  of  explaining 
the  disappearance  of  all  trace  of  the  nucleus  of  the  parent  cell  presents 
no  difficulties.  Among  the  majority  of  writers  who  accept  the  origin 
from  nucleated  cells,  the  theories  regarding  the  disappearance  of  the 
nucleus  are  various  but  none  has  been  fully  demonstrated. 

Kolliker/  Bizzozero,'^  Neumann,'  Lowit,  Foa,  and  many  recent  ob- 
servers believe  that  the  nucleus  gradually  disappears  in  the  cell.  The 
difficulty  in  accepting  this  opinion  lies  in  the  fact  that  Avhile  red  cells 
with  rather  small  nuclei  are  abundant  in  red  marrow,  the.  Jinal  stac/ex 
of  the  disappearance  of  the  nucleus  are  traced  only  with  difficulty.  Yet 
Schmidt,  Spuler,  Israel  and  Pappenheim,  and  Masslow,  claim  to  have 
found  these  final  stages  in  abundance.  Eiirlich  believes  that  the 
nucleus  of  the  normoblast  is  extruded,  while  that  of  the  megaloblast 
fades  within  the  cell. 

Rindfleish  first,  and  later  Howell,  described  fully  the  shrinkajje  and  final 
extrusion  of  the  compact  nuclei  of  red  cells  in  man,  mammals,  and  amphibia. 
Van  der  Stricht,  Kostianecki,i  Saxer,  Albrecht,  Disse,  Muir,  and  others 
find  that  after  considerable  shrinkage  the  nucleus  may  become  compact  and 
homogeneous  or  may  be  fragmented,  but  it  is  eventually  extruded  and  either 
breaks  up  in  the  plasma  or  is  euglobed  by  leucocytes,  giant  cells,  or  endo- 
thelia.  The  significance  of  this  somewhat  remarkable  phenomenon  has  not 
been  fully  demonstrated.  The  opponents  of  this  theory  claim  that  free 
nuclei  are  seen  in  sufficient  numbers  to  account  for  the  production  of  many 
red  cells,  only  in  smears  of  the  marrow,  but  scantily  in  sections.  The  writer 
finds  this  objection  valid,  unless  the  destruction  of  extruded  nuclei  is  more 
rapid  than  Ave  have  any  good  reason  to  believe. 

As  a  modification  of  the  "extrusion"  theory,  Malassez,  Fellner,  and 
Duval  believe  that  the  nucleated  red  cell  extrudes  a  portion  of  its  substance 
in  the  form  of  a  red  disc  entirely  free  from  nuclear  material,  but  the  histology 
of  the  marrow  offers  insufficient  ground  for  belief  in  such  a  process. 

Engeli  holds  that  mcgaloblasts  produce  megalocytes  by  gemmation,  leav- 
ing normoblasts,  from  which  the  nuclei  are  extruded.  Mondino  and  Sala 
find  evidence  that  the  nuclear  material  finally  diffuses  along  the  periphery 
of  the  cell,  where  it  undergoes  a  chemical  change  which  causes  it  to  lose  its 
affinity  for  basic  dyes.  Obrastzow  ~  also  believes  that  the  nucleus  persists  in 
diffuse  form  in  the  disc,  and  that  it  may  reappear  as  a  result  of  post-mortem 
processes.  Finally,  Buttcher  and  Brandt  claim  that  the  nucleus  persists 
and  may  be  demonstrated  in  the  normal  red  veils  by  certain  staining 
methods,  while  Wooldridge,  and  Botazzi  and  Capelli.  by  chemical  analy.sis, 
are  always  able  to  demonstrate  nuclear  material  in  the  red  cells. 

While  the  weight  of  opinion  and  evidence  seems  to  favor  the  grad- 
ual fading  of  the  nucleus  within  the  cell,  and  while  it  can  hardly  be 
denied  that  extrusion  frequently  occur.s,  there  is  abundant  evidence  to 
show  that  the  red  cell  is  not  entirely  devoid  of  nuclear  material.  The 
chemical  analysis  of  the  stroma  of  these  cells  decidedly  favors  the 
presence  of  nuclear  elements  (Lilienfeld,  Wooldridge) ;  the  appearance 
of  degenerating  cells  strongly  suggests  a  nuclear  remnant,  and  the  em- 


ERYTHROCYTES.  153 

ploymeut  of  recent  stains,  neutral  red,  polychrome  blue,  frequently 
yields  the  specific  reaction  of  chromatin  in  the  centers  of  slightly 
altered  red  cells.  The  recent  studies  of  Maximow  indicate  that  while 
the  bulk  of  the  nucleus  is  extruded,  a  portion  remains  in  finely  granu- 
lar form  and  imparts  a  basic  staining  quality  to  the  centers,  specially  of 
young  red  cells. 

Seats  of  Formation  of  Red  Cells. — («)  In  the  early  embryo  the  pro- 
duction of  red  cells  follows  the  development  of  capillary  blood  vessels 
in  many  tissues.  Very  soon  the  rudimentary  liver  and  lymph  nodes 
make  their  appearance  and  in  them  the  function  of  red  cell  formation 
is  gradually  concentrated. 

(6)  In  the  fully  developed  embryo,  the  majority  of  investigators  locate 
the  chief  formation  of  red  cells  in  the  liver,  to  a  less  extent  in  the 
spleen,  while  the  bone  marrow,  which  is  at  first  less  prominent  in  this 
process,  gradually  absorbs  the  function,  and  in  the  human  fetus  at 
birth  represents  its  chief  seat. 

In  most  infants  at  birth,  however,  the  liver,  and  less  constantly  the 
spleen,  are  found  to  contain  many  nucleated  red  cells,  while  in  some 
cases  the  proportion  of  these  cells  in  the  liver  is  very  large  and  nu- 
merous small  collections  of  them  may  be  found  scattered  along  the 
portal  capillaries. 

(c)  In  Extra-uterine  Life. — The  fact  that  the  red  marrow  is  probably 
the  exclusive  depot  of  formation  of  red  cells  in  the  adult  was  discov- 
ered almost  simultaneously  in  1868  by  Neumann^  and  by  Bizzozero.^ 

This  original  claim  has  been  uniformly  substantiated  by  those  later 
observers  who  recognize  as  erythroblasts  only  those  cells  which  contain 
a  trace  of  Hb.  Others,  as  Lowit  and  Muller,  Gibson,  Foa,  Saxer,  who 
trace  the  red  cells  back  to  colorless  cells,  regard  all  lymphoid  tissues 
as  probable  sources  of  erythroblasts. 

In  pathological  conditions  it  has  been  shown  that  the  spleen  (Bizzo- 
zero,^  Neumann,^  Howell)  in  the  human  adult  may  resume  its  embry- 
onal function  of  red  cell  formation,  as  indicated  by  the  presence  of 
many  nucleated  red  cells.  Under  similar  conditions  it  has  been  shown 
that  the  limits  of  red  marrow,  normally  confined  to  the  flat  bones,  ribs, 
vertebrse,  and  upper  and  lower  thirds  of  the  long  bones,  may  be  ex- 
tended throughout  nearly  the  entire  cavities  of  all  bones  except  those 
of  the  feet.     (JSTeumann,  Litten  and  Orth,  Bizzozero  and  Salvioli.) 

In  infancy,  and  up  to  the  sixteenth  year,  the  cavities  of  all  bones 
contain  almost  entirely  red  marrow,  but  there  are  considerable  vari- 
ations in  the  proportions  of  lymphoid  and  fat  tissue  in  the  shafts  of  the 
long  bones.  It  is  probable  that  in  most  healthy  infants  the  formation 
of  red  cells  is  already  limited  to  the  lymphoid  marrow,  but  considerable 
numbers  of  nucleated  red  cells,  often  grouped  in  islands,  are  rather 
frequently  to  be  found  in  the  spleen  and  liver  of  apparently  healthy 
asphyxiated  infants.  In  the  acute  and  chronic  anemias  of  infancy  and 
childhood,  the  facility  with  which  the  spleen  and  liver  resume  their 
former  role  of  red  cell  production  partly  explains  the  special  involve- 
ment of  these  organs  in  such  diseases. 


154  DEVELOPMENT  OF  BLOOD   CELLS. 

LEUCOCYTES. 

Development  of  Leucocytes. — The  earliest  indications  of  the  for- 
mation of  leucocytes  are  seen  in  the  presence  of  primary  wandering  cells^ 
of  mesodermal  origin,  which  are  found  principally  in  the  loose  connec- 
tive tissues  of  the  early  embryo.  The  specific  quality  of  these  wander- 
ing cells  must  stand  as  one  of  the  fundamental  facts  connected  with  the 
development  of  blood  cells.  Though  of  mesodermal  origin  they  are 
from  the  first  quite  distinct  in  morphology  and  apparently  in  function 
from  the  capillary  endothelium  and  fixed  connective  tissue  cells.  The 
primary  wandering  cells  are  of  large  size,  8-9  li  (Saxer),  with  a  single 
large  nucleus  containing  one  or  more  nucleoli  and  with  a  moderate 
quantity  of  finely  granular  slightly  acidophile  protoplasm.  Their  de- 
velopment has  been  traced  by  H.  E.  Ziegler  to  masses  of  mesodermal 
cells  surrounding  the  cords  from  which  the  capillaries  are  formed.  It 
thus  appears  that  the  parent  leucocytes  lie  originally  outside  the  vessek^ 
into  which  they  make  their  way  by  virtue  of  ameboid  poAvers. 

The  identity  of  the  primary  leucocytes  with  the  primary  wandering- 
cells  has  been  generally  accepted,  but  Schmidt,  Bonnet,  and  others, 
claim  that  leucocytes  are  derived  from  the  capillary  endothelium.  The 
weight  of  evidence,  however,  is  much  against  this  view,  which  inserts 
the  highly  specialized  endothelial  cell  as  a  transition  stage  between  the 
primary  mesodermal  cell  and  the  leucocytes.  An  isolated  position  also 
is  assumed  by  v.  Davidoff,  Maurer,  and  others,  who  believe  the  leuco- 
cytes to  be  direct  derivatives  of  the  epithelial  cells,  principally  of  the 
intestine.  This  view  is  based  upon  the  appearance  of  lymphocytes 
in  and  between  the  epithelial  cells  lining  many  mucous  surfaces,  which 
has  been  repeatedly  and  fully  explained  as  an  infiltration  by  leucocytes, 
not  a  production  of  new  lymphocytes  from  these  cells.     (Saxer.) 

The  white  blood  cells  of  vertebrates  make  their  ai)pearance  in  the 
circulation  only  after  the  development  of  an  extensive  vascular  system 
and  long  after  the  red  cell  formation  has  been  fully  established.  In 
the  lower  vertebrates  their  absence  has  been  noted  nine  weeks  (Ziegler') 
after  the  appearance  of  red  cells,  but  Hay  em  found  them  in  frogs' 
blood  34  days  after  the  appearance  of  red  cells.  The  time  of  their  ap- 
pearance in  the  blood  of  the  human  embryo  has  not  been  accurately 
fixed.  Gulland  finds  leucocytes  in  lymph  vessels  in  the  human  em- 
bryo of  one  and  one-half  inches  in  length.  In  form  the  earliest  leuco- 
cytes of  the  embryonal  circulation  are  the  small  and  medium-sized 
basophilic  lymphocytes. 

Process  of  Development  of  Leucocytes  from  Primary  Wander- 
ing Cells. — Most  observers  find  that  the  primary  wandering  cells  pro- 
duce by  mitotic  division  one  or  more  generations  of  colorless  cells 
which  gradually  approach  in  morphology  the  early  basophilic  leuco- 
cytes of  the  circulation.  Most  of  the  obscurity  which  still  surrounds 
the  early  development  of  red  and  white  blood  cells  is  connected  with 
this  stage  of  the  process,  and  the  numberless  conflicting  opinions 
have    resulted   from    the    different   interpretations    placed    upon    the 


DEVELOPMENT  OF  LEUCOCYTES  FROM  WANDERING   CELLS.   155 

intermediate  stages  between  primary  wandering  cells  and  circulating 
blood  cells. 

Denys,  Lowit/  Ziegler,^  v.  d.  Stricht,  and  others  claim  that  red  cells 
and  leucocytes  develop  from  separate  series  of  cells  which  have  become 
differentiated  from  the  primary  mesodermal  cells  with  the  first  appear- 
ance of  blood  and  blood  vessels. 

Kostianecki,"  Muller,  Schmidt,  Saxer,  and  others,  believe  that  the 
primary  wandering  cell  persists  in  the  blood-forming  organs  as  the 
parent  of  both  red  and  white  cells. 

It  is  not  impossible  to  partially  reconcile  these  opposing  views. 
While  the  exhaustive  studies  of  Saxer  seem  to  leave  no  room  to  doubt 
the  common  origin  of  embri/onal  red  and  white  cells,  it  by  no  means 
follows  that  the  blood  cells  of  the  adult  may  be  traced  to  a  common 
origin.  Several  generations  (3-4,  Saxer),  each  multiplying  by  indirect 
division,  are  required  before  the  primary  wandering  cell  is  transformed 

Fig.  20. 


Primary  wanderinfj  Mt^^  Enihryoiidl Liver  ftc. 

cell  ^H^^^         Dis(ippe<(rs  in  late  foetal  life 


Saxer'a  fl  orc/er 

in  order 


into  red  cells  or  leucocytes.  It  is  quite  possible  that  the  first  mem- 
bers of  the  series,  including  the  primary  mesodermal  cells,  long  persist 
in  the  embryo,  but  disappear  in  the  adult,  in  whom,  therefore,  no  com- 
mon cell  of  origin  of  erythrocytes  and  leucocytes  can  be  demonstrated. 
A  review  of  the  principal  minute  studies  in  this  field  seems  to 
the  writer  to  warrant  the  above  general  conclusion  in  regard  to  the 
relation  of  red  and  white  blood  cells.  That  all  blood  cells  of  the  em- 
bryo can  be  traced  to  a  common  origin  seems  to  be  fully  proven. 
Although  the  exhaustive  studies  of  Denys,  v.  d.  Stricht,  and  Lowit, 
were  largely  upon  embryonal  tissues,  the  morphological  criteria  on 
which  they  separate  primary  leucoblasts  from  erythroblasts  do  not  ap- 


156  DEVELOPMENT  OF  BLOOD   CELLS. 

pear  sufficiently  distinct  to  convince  other  observers,  while  the  clenion- 
stration  by  Saxer  and  others  of  earlier  mitotic  cells  in  the  same  em- 
bryonal tissues  seems  to  show  that  the  common  cell  of  origin  persists 
in  the  fetal  liver.  Muller's  studies  of  leukemic  blood  in  Avhich  he 
seems  to  have  traced  leucocytes  and  red  cells  to  a  common  origin  in 
the  adult  indicates  that  this  pathological  condition  involves  a  reversion 
to  the  embryonal  type  of  blood  formation,  but  does  not  prove  that  a 
common  mother  cell  of  both  red  and  white  blood  corpuscles  persists  in 
the  normal  adult  marrow.     (See  Fig.  20.) 

Cellular  Divisiox  in  the  Development  of  Leucocytes. — 
Since  the  full  demonstration  by  Flemming  of  numerous  mitotic  figures 
in  the  cells  of  the  lymph  follicles,  karyokinesis  has  been  accepted  as 
the  chief  method,  and  many  claim  it  to  be  the  only  method,  of  multi- 
plication of  leucocytes. 

This  view  has  been  actively  combated  by  Lowit,  who  finds  that  while 
erythroblasts  multiply  by  mitosis,  leucoblasts  follow  a  modified  form  of  the 
process  which  he  calls  divisio  indireda  per  granula.  This  author  has  very 
ably  and  successfully  defended  the  importance  of  direct  division  in  mammals 
and  lower  vertebrates,  and  subsequent  authors  have  admitted  that  this 
method  is  of  "very  widespread''  (Saxer)  occurrence  among  leucocytes. 
Direct  division  appears  to  be  of  special  importance  in  the  development 
of  the  giant  cells  of  the  embryonal  liver  and  adult  marrow,  which  play 
an  important  but  somewhat  obscure  part  in  blood  formation.  Indirect 
fragmentation  is  a  term  applied  to  a  somewhat  peculiar  modification  of  the 
usual  process  of  nuclear  division  described  by  many  authors,  especially  by 
Arnold.  1 

While  the  formation  of  leucocytes  occurs  principally  in  the  blood- 
forming  organs,  many  have  found  in  the  circulating  blood,  and  espe- 
cially in  the  lymph,  evidences  of  active  multiplication  by  mitosis  and 
more  frequently  by  amitosis.      (Spronk  and  Prins,  Lowit,'  AVertheim.) 

Sites  of  Origin  of  Embryonal  Leucocytes. — Before  the  leucocytes 
begin  to  appear  in  the  circulation  mitotic  figures  are  abundantly  seen 
in  the  primary  wandering  cells  in  various  situations.  These  are  gath- 
ered in  groups,  first  in  the  loose  connective  tissues  of  various  regions 
where  lymph  nodes  subsequently  develop,  but  the  chief  seat  of  the  pro- 
duction of  leucocytes,  as  of  red  cells,  is  found  in  the  embryonal  liver. 
In  both  situations,  the  wandering  cells  are  found  ii\  the  lymph  and 
blood  capillaries,  in  the  interstices  of  the  connective  tissues,  and  be- 
tween the  liver  cells.  In  later  embryonal  life  the  formation  of  leuco- 
cytes is  gradually  transferred  from  the  liver  to  the  lymphoid  and 
adenoid  tissues,  as  indicated  by  the  development  of  the  lymph  nodes, 
spleen,  marrow,  and  thymus.  While  the  majority  of  observers  be- 
lieve that  these  tissues  are  at  all  times  developed  by  the  proliferation 
of  extra-vascular  wandering  cells  and  leucoblasts,  Stohr  and  Gulland 
believe  that  these  cells  multiply  principally  tcitldn  the  vessels  and  sub- 
sequently wander  out  at  certain  localities  where  they  collect  to  form 
lymph  nodes. 

Formation  of  Leucocytes  in  Adult  Life.— Under  normal  condi- 


THE  NEUTROPHILE  LEUCOCYTES.  157 

tions  the  reproduction  of  leucocytes  in  the  adult  is  limited  to  the  lym- 
phoid structures,  including  the  lymph  nodes,  spleen,  and  marrow. 

Appearance  of  Different  Varieties  of  Leucocytes. — In  the  later 
months  of  fetal  life,  the  blood  begins  to  show  the  presence  of  other 
varieties  of  leucocytes  besides  the  lymphocytes.  The  minute  mor- 
phology of  these  early  cells  and  the  exact  time  of  their  appearance  is  not 
known,  but  it  is  certain  that  all  varieties  seen  in  the  adult  are  present 
at  birth,  and  there  is  much  evidence  to  show  that  long  before  this 
period  the  development  of  several  distinct  types  of  leucocytes  is  well 
established  and  their  formation  at  least  partially  limited  to  certain 
viscera.  From  the  considerations  of  the  previous  part  of  this  section 
it  is  evident  that  all  forms  of  leucocytes  must  have  a  common  origin 
in  the  primary  wandering  cell,  but  it  does  not  by  any  means  follow  tJiat 
the  various  forms  of  leucocytes  in  the  adult  are  developinental  forms  of  one 
series,  although  this  view  has  been  generally  accepted  as  correct. 

The  Basophile  Leucocytes. — These  cells  are  the  direct  descend- 
ants of  the  first  embryonal  leucocytes,  and  are  uudoubtedly  produced,  in 
the  adult  as  in  the  embryo,  by  the  mitotic  division  of  cells  lying  in  the 
proliferation  zones  of  lymph  follicles,  and  diffusely  in  all  adenoid  tis- 
sues. Virchow  regarded  the  small  basophile  cells  (lymphocytes)  as 
originating  in  the  lymph  nodes  and  the  large  basophile  cells  (spleno- 
cytes)  as  derivatives  of  the  spleen  ;  but  this  distinction  has  not  been 
supported.  It  seems  more  probable,  though  by  no  means  certain,  that 
most  or  all  of  the  larger  basophilic  leucocytes  of  normal  blood  are  de- 
veloped from  lymphocytes.  Kanthaok  and  Hardy  endeavored  to  sub- 
divide this  class  into  basophile  and  hyaline  cells,  the  former  being 
"  tissue  cells  "  and  rarely  appearing  in  the  blood,  the  latter  identical 
with  the  ordinary  small  and  large  lymphocytes.  Kanthack's  coarsely 
granular  basophile  cell  is  the  "  mast-cell,^'  which  has  no  connection 
with  the  lymphocytes,  but  his  finely  granular  basophile  cell  has  not 
been  recognized  as  distinct  from  the  hyaline  cells  whose  protoplasm  is 
not  strictly  hyaline  but  reticulated,  and  which  undoubtedly  originates 
in  the  lymphoid  organs. 

The  MAST-CELLS,  which  contain  large,  strongly  basophilic  granules, 
are  classed  by  Kanthack  as  celomic  (tissue)  cells.  They  are  quite  dif- 
ferent in  appearance  from  the  coarsely  granular  basophilic  cells  of 
chronically  inflamed  tissues  and  their  exact  origin  has  not  been  ex- 
plained.    (Cf.  "  Mast-cells,"  Section  on  Leukemia.) 

The  Neutrophile  Leucocytes. — The  time  of  appearance  of  these 
cells  in  the  human  embryo  is  not  known.  Saxer  finds  in  the  sheep's 
embryo  of  4.5  cm.,  in  connective  tissues  and  scantily  in  the  lymph, 
polynuclear  leucocytes  identical  in  appearance  with  those  of  the  adult 
animal. 

If  the  polynuclear  leucocytes  are  developed  from  lymphocytes,  the 
seat  of  their  production  in  the  infant  at  birth  is  of  course  coextensive 
with  that  of  lymphocytes,  but  if  polynuclear  neutrophile  cells  are  de- 
rived as  a  separate  series  from  the  neutrophile  myelocytes,  their  forma- 
tion is  limited,  at  birth  and  thereafter,  to  the  red  marrow.     Whichever 


158  DEVELOPMENT  OF  BLOOD  CELLS. 

view  may  be  correct,  it  is  certain  that  the  neiitrophile  myelocytes  are 
largely  concerned  in  the  formation  of  these  cells,  and  that  the  marrow 
is  the  chief  seat  of  their  production. 

The  opinion  widely  held  that  neutrophile  leucocytes  are  developmental 
forms  of  the  mononuclear  basophile  cells  still  lacks  any  definite  support. 
That  they  are  certainly  produced  by  mitotic  division  of  neutrophile  myelo- 
cytes has,  however,  been  placed  beyond  question,  by  the  constant  appear- 
ance of  increased  numbers  of  mitotic  myelocytes  in  leukemia  and  leucocytosis. 
The  larger  size,  distinctly  vesicular  nucleus,  basophilic  protoplasm,  and  in- 
variable absence  of  neutrophile  granules  in  the  most  typical  examples  of  the 
so  called  "transitional  leucocytes"  cannot  be  reconciled  with  the  view  that 
these  cells  are  ever  transformed  into  neutrophile  leucocytes.  Some  have  re- 
ferred to  myelocytes  deficient  in  neutrophile  granules  as  transitional  forms, 
but  in  leukemia  where  such  cells  are  common,  a  deficiency  of  neutrophile 
granules  is  very  frequent  in  both  myelocytes  and  polynuclear  leucocytes. 
Again,  if  basophile  leucocytes  form  neutrophile  cells  it  is  difficult  to  see  why 
numerous  transition  forms  are  not  found  in  lymphatic  leukemia  where 
basophile  cells  are  excessively  numerous,  but  neutrophile  are  abnormally 
scarce.  Lowit  here  resorts  to  the  suggestion  that  the  further  development 
of  these  cells  is  inhibited  by  changes  in  the  plasma.  Yet  in  myelogenous 
leukemia  no  such  changes  in  the  plasma  prevent  the  transformation  of 
myelocytes  into  polynuclear  leucocytes  which  here  often  outnumber  the 
myelocytes. 

Out  of  the  constantly  accumulating  evidence  which  goes  to  establish  the 
specific  qualities  of  different  leucocytes  may  be  mentioned  the  studies  of 
Zenoni,  who  found  no  change  in  the  proportion  of  neutrophile  cells  during 
very  marked  variations,  experimentally  induced,  of  the  basophile. 

The  Eosinophile  Leucocytes. — These  cells  very  early  become 
differentiated  from  the  primary  leucocytes,  having  been  found  in  the 
chick's  blood  on  the  fifth  day  of  incubation  (Engel  ^)  and  in  the  human 
thymus  and  lymph  nodes  before  the  appearance  of  bone  marrow  (Schaf- 
fer,  Gulland).  Though  it  was  early  found  tliat  they  are  specially  abund- 
ant in  the  marrow,  their  very  wide  distribution  in  the  tissues  shows  that 
the  conditions  essential  to  their  development  are  not  limited  to  any  single 
organ  or  tissue.  The  discovery  of  mitotic  division  of  eosinophile  leuco- 
cytes, first  reported  by  Muller  and  subsequently  verified  by  many  others, 
would  seem  sufficient  proof  that  these  cells  constitute  a  distinct  self-per- 
petuating series.  Nevertheless  the  majority  of  current  writers  either 
tacitly  accept  or  actively  argue  that  the  eosinophile  are  derived  from  the 
neutrophile  granules  of  polynuclear  leucocytes.  Demonstration  of  the 
truth  of  this  view  is  at  present  entirely  lacking.  Only  Gulland  attempts 
to  describe  transitional  stages  between  neutrophile  and  eosinophile  gran- 
ules in  embryonal  blood  cells,  but  his  claims  have  not  only  not  been  veri- 
fied but  are  distinctly  contradicted  by  the  results  of  the  vast  majority  of 
observers,  who  have  failed  to  find  any  such  transition  forms  in  the  adult. 
On  the  other  hand  there  is  abundant  physiological,  morphological,  and 
microchemical  evidence  to  show  that  eosinophile  leucocytes  are  not  derived 
from  neutrophile. 

Physiologically,  the  eosinophile  cells  are  celomic  tissue  cells,  finding 
their  natural  habitat  in  the  tissues  and  not  in  the  blood,  whereas  the 
neutrophile  leucocytes  are  chiefly  hemic  cells  occurring  almost  exclu- 


THE  BLOOD  PLATES.  159 

sively  in  the  blood.  Moreover,  since  these  cells  certainly  multiply  by 
mitosis,  it  is  unnecessary  and  contrary  to  analogy  to  suppose  that  any 
other  method  of  development  or  formation  exists.  The  morphological 
evidence  includes  the  fact  that  transitional  granules  have  not  been 
demonstrated  ;  that  the  nuclei  of  the  two  cells  have  rather  distinctive 
characters,  and  that  the  granules  are  integral  parts  of  the  cytoreticulum 
(Heidenhain,  Gulland),  and  not,  as  has  been  supposed,  excretory  prod- 
ucts in  the  cell.  The  microchemical  evidence  shows  that  the  eosino- 
phile  granules  yield  Lilienfeld's  and  Monti's  reaction  for  phosphorus 
(Sherrington),  contain  iron  (Barker),  and  give  the  vanillin  and  alde- 
hyde reactions  of  Weiss,  none  of  which  characters  have  been  demon- 
strated in  ueutrophile  granules. 

THE    BLOOD    PLATES. 

The  blood  plates  were  first  described  by  Donne,  in  1842,  who  found 
them  in  blood  upon  the  addition  of  water  and  regarded  them  as  parti- 
cles of  globulin  derived  from  the  red  cells.  In  1847  Zimmermann 
found  in  defibriuated  blood  certain  "  elementary  granules,"  at  first 
about  1  /^  in  diameter,  but  gradually  increasing  in  size,  and,  as  he  be- 
lieved, eventually  becoming  red  cells. 

The  first  complete  descriptions  were  given  by  Schulze,  Kolliker,^ 
Ranvier,  and  Bizzozero,*  and  later  by  many  authors. 

They  are  circular  or  ovoid,  colorless,  homogeneous,  or  granular 
bodies,  about  1-3  /j.  in  diameter,  usually  showing  no  nuclear  portion, 
and  staining  lightly  by  both  basic  and  acid  dyes.  The  common  im- 
pression that  they  disappear  promptly  after  shedding  is  true  only  of 
the  spindle  cells  of  the  blood  of  lower  animals,  while  human  blood- 
plates  are  scanty  in  fresh  blood  and  increase  in  number  upon  standing. 
They  are  extremely  cohesive  and  apparently  of  high  gravity,  and 
since  they  collect  in  masses  from  which  the  fibrinous  threads  of  co- 
agulating blood  commonly  radiate,  they  are  supposed  to  take  an  im- 
portant part  in  the  formation  of  fibrin. 

On  account  of  their  uncertain  morphology  and  origin,  attempts  to 
enumerate  these  bodies  have  not  been  very  successful.  In  normal 
blood  they  may  be  said  to  vary  between  1 80,000  (Fusari)  and  500,- 
000  (Pruss).  Estimates  of  their  numbers  based  upon  the  general 
appearance  of  the  blood  indicate  that  they  are  specially  abundant  in 
afebrile  anemias,  leukemia,  hemorrhages,  and  that  they  are  deficient 
in  febrile  diseases,  malaria,  and  after  the  administration  of  various 
poisons.     (Afanissiew,  Limbeck,  Fusari,  Pizziui.) 

The  significance  of  the  so-called  "  third  corpuscles "  of  human 
blood,  the  blood  plates,  appears  to  have  been  greatly  obscured  by  the 
discovery  in  the  blood  of  frogs  by  Recklinghausen,  and  of  birds  by 
Hayem,  and  Bizzozero  and  Torre,  of  small  spindle-shaped  elements, 
which  differ  from  red  cells  in  the  absence  of  hemoglobin  and  from 
leucocytes  in  their  simple  oval  nucleus  and  non-ameboid  protoplasm, 
and  which  have  been  reofarded  as  the  homologue  of  the  human  blood 


160  DEVELOPMENT  OF  BLOOD   CELLS. 

plates.  Lowit"  classes  these  spindle  cells  with  leucocytes.  Muller 
believes  them  to  be  peculiar  elements  without  relation  to  either  red  or 
white  cells.  Rauvier  regarded  them  as  loosened  vascular  endothelia. 
The  conclusion  of  Recklinghausen,  Gobulew,  Schlarewsky,  Bizzozero, 
Hayera,  Vulpian,  Eberth  and  Schinimelbusch,  that  these  cells  are 
analogues  of  the  blood  plates  is  the  chief  ground  for  the  belief  in  the 
existence  of  a  third  corpuscle  in  human  blood. 

When  the  evidence  derived  from  the  examination  of  human  blood  is 
considered,  it  becomes  clear  that  the  existence  of  a  third  cellular  body 
is  without  proof.  Bizzozero's  convincing  demonstration  of  the  pres- 
ence of  extremely  fragile  bodies  in  the  blood  of  the  frog's  mesentery 
has  naturally  never  been  repeated  in  human  blood,  and  the  dissimi- 
larity between  human  blood  plates  and  the  spindle  cells  of  the  frog 
requires  much  more  cogent  evidence  of  the  relation  of  these  two  bodies 
than  has  yet  been  furnished.  Consequently  later  investigators  have 
with  apparent  success  endeavored  to  show  that  the  blood  plates  are  not 
cells  but  detritus  of  cells  or  of  plasma.  Howell,  Gibson,  and  Hlava,  re- 
gard the  blood  plates  as  fragments  of  the  nuclei  of  disintegrated  leu- 
cocytes. Lowit  believes  many  of  them  to  be  precipitated  globulin 
particles,  and  others  to  be  fragments  of  degenerating  leucocytes.  On 
account  of  their  chemical  composition  Lilienfeld  holds  that  they  con- 
sist of  nuclein,  and  that  they  are  derived  principally  from  the  nuclei 
of  disintegrated  leucocytes.  Czermak  finds  them  abundantly  in  the 
proliferation  zones  of  lymphoid  organs,  and  wdth  Mondino  and  Sala 
believes  them  to  be  fragments  of  the  nuclei  of  colorless  cells. 

The  studies  of  Klebs,  Eugel,  Bremer,  Wlassow,  Arnold,-  Maximow, 
and  others,  have  placed  beyond  doubt  the  opinion  that  the  chief  source 
of  blood  plates  is  by  the  extrusion  from  red  cells  of  masses  or  chains 
of  globular  material,  which  give  many  of  the  reactions  of  the  nucleo- 
proteids.  While  this  process  may  be  observed  in  almost  every  dry 
specimen  stained  by  methylene-blue  (Plate  II.,  Fig.  2),  it  appears  to 
be  favored  by  proximity  to  leucocytes,  may  be  accelerated  by  many 
reagents,  and  is  probably  especially  frequent  in  young  red  cells. 

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Rindfleisch.     Archiv  f.  micr.  Anat.,  1879,  Bd.  17. 

Saxer.     Anat.  Hefte,  Bd.  VI.,  1896. 

Schajer.     Quain's  Anat.  Hist.,  1891,  p.  218. 

Schaffer.     Cent.  f.  d.  med.  Wissen.,  1891. 

M.  Schmidt.     Ziegler's  Beitriige,  1891,  Bd.  XI. 

Schlaretvsky.     Cent.  f.  med.  Wissen.,  1867. 

Schulze.     Arch.  f.  micr.  Anat.,  Bd.  1865. 

Sherrington.     Proc.  Royal  Soc,  1894,  Vol.  55,  p.  161. 

Spronk,  Prins.     Cited  by  Saxer. 

Spuler.     Archiv  f.  micr.  Anat.,  Bd.  40. 

Stohr.     Text-book  of  Histology. 

V.  d.  Stricht.     Archiv  de  Biologic,  XII.,  1892,  p.  199. 

Strieker.     Gewebelehre. 

Vulpian.     Compt.  Rend.  Soc.  Biol.,  1877. 

Wertheim.     Zeit.  f.  Heilk.,  1891,  Bd.  XII. 

Wissosky.     Archiv  f.  micr.  Anat.,  1877,  Bd.  13. 

Wlassnw.     Ziegler's  Beitriige,  Bd.  15. 

Wooldridge.     Chemistry  of  Blood,  London,  1893. 

Ziegler.     '  Ber.  d.  naturforscher  Gesell.  Freiburg,  1889,  Bd.  IV.,  171.     ^Archiv 
f.  micr.  Anat.,  Bd.  30. 

Zivimennan.     Rust's  Mag.  f.  d.  gesam.  Heilkunde,  1846,  Bd.  66,  H.  2. 

11 


i 


PART  11. 
SPECIAL  PATHOLOGY  OF  THE  BLOOD. 

CHAPTER    VI. 
CHLOROSIS. 

Chlorosis  is  a  primary  anemia  occurring  almost  exclusively  in 
young  women,  rarely  in  young  men,  resulting  from  defective  hemato- 
genesis  and  affecting  principally  the  hemoglobin  but  secondarily,  also 
the  number  of  red  cells. 

Etiology. — The  studies  of  the  etiology  of  chlorosis  having  estab- 
lished a  great  variety  of  predisposing  and  exciting  causes,  and  rendered 
it  evident  that  the  disease  results  under  very  many  diverse  conditions, 
have  left  the  essential  factor  in  the  evolution  of  the  disease  undeter- 
mined. On  this  account  some  are  inclined  to  regard  chlorosis  as  a 
symptomatic  anemia,  holding  the  peculiar  clinical  characters  of  the 
disease  to  result  from  the  age  and  constitution  of  the  individuals  in 
whom  it  occurs.     (Kruger.) 

Regarding  the  general  causes  a  number  of  theories,  supported  by 
many  important  facts,  have  been  brought  to  light. 

Hypoplasia  of  the  arterial  system  is  an  anatomical  ground- 
work shown  by  Rokitansky  and  Virchow  to  exist  in  a  certain  group 
of  cases.  This  hypoplasia  may  affect  only  the  heart  and  larger  arteries 
or  the  genital  organs  as  well,  or  is  frequently  associated  with  the 
other  developmental  anomalies  of  the  conditutlo  lymphatica.  More  re- 
cent studies  (Paltauf,  Ortner,  Fraentzel)  indicate  that  the  congenitally 
small  heart  and  aorta  are  more  closely  associated  with  the  "  constitutio 
li/inphatica'^  and  with  cardiac  disease,  than  with  chlorosis.  This  hypo- 
plasia has  been  found  in  subjects  never  suifering  from  chlorosis,  and 
the  majority  of  chlorotics  give  no  other  evidence  of  such  vascular 
anomalies  and  make  complete  and  permanent  recovery. 

Intestinal  autointoxication  was  first  suggested  as  the  essential 
cause  of  chlorosis  by  Hoffman,  and  this  theory  has  been  supported  on 
various  clinical  and  pathological  grounds  by  Duclos,  Clark,  Nothnagel, 
Bouchard,  and  many  others.  Bunge's  authority  has  lent  some  force  to 
the  autotoxic  theory  as  this  investigator  holds  that  the  blood  obtains 
iron  solely  from  the  nucleo-albumens,  the  iron  from  which  is  combined 
with  sulphur  during  intestinal  putrefaction  and  thus  becomes  nonab- 
sorbable. In  chlorosis  the  iron  administered  by  mouth  combines  with 
the  H^S  and  permits  the  normal  absorption  of  the  nucleo-albumens. 


164  SPECIAL  PATHOLOGY  OF  THE  BLOOD. 

This  theory  has  been  completely  set  aside  by  the  demonstration  by 
V.  Noorden/  Rethers,  Moruer,  and  Lipraan  and  Wulf,  that  in  chlorosis 
increased  intestinal  putrefaction  is  not  commonly  present,  nor  is  there 
increased  excretion  of  the  derivatives  of  Hb.  Stockman  showed, 
moreover,  that  sulphate  of  iron  will  cure  the  disease,  while  bismuth  and 
some  other  absorbents  of  H^S  will  not.  Intestinal  intoxication  can, 
therefore,  figure  in  only  a  limited  group  of  cases. 

V.  Hosslin,  finding  marked  increase  of  iron  in  the  feces  of  some 
chlorotic  patients,  concluded  that  the  blood  changes  result  from  small 
multiple  intestinal  hemorrhages.      Luton  accepts  this  theory. 

Functional  disturbances  of  the  nervous  system  have  from 
the  first  been  actively  maintained  as  prominent  or  exclusive  etiological 
factors  in  chlorosis.  The  train  of  events  here  involved  is  variously 
explained.  Murri  supposes  that  there  is  a  vasomotor  disturbance 
arising  from  the  generative  organs,  and  causing  changes  first  in  the  rate 
of  flow,  later  in  the  chemistry  of  the  blood.  This  theory  represents 
the  culmination  of  opinion  as  handed  down  by  the  older  physicians. 
(Trousseau,  cf.  Lloyd  Jones.)  According  to  Meinert  the  nervous  in- 
fluence arises  from  irritation  of  the  abdominal  sympathetic  and  results 
from  gastropfosis.  This  observer  has  brought  together  very  strong  evi- 
dence to  show  that  in  one  group  of  cases  the  above  condition  must  be 
an  important  factor  in  the  coincident  anemia.  Kruger  believes  that 
hypertrophy  of  the  spleen  commonly  associated  with  chlorosis  (Fuhrer, 
Scharlau,  Chvostek,  Clement,  Grawitz,  Rummo,  and  Dorri)  is  an  indi- 
cation of  disturbance  of  function  in  this  organ  which  results  in  an  in- 
creased destruction  of  Hb.  This  disturbance  of  function  is  believed  to 
arise  through  irritation  of  the  sympathetic,  in  the  genital  organs, 
stomach,  intestines,  etc. 

Predisposing  Causes. — The  almost  exclusive  occurrence  of  the 
disease  near  the  establishment  of  menstruation  must  prove  any  theory 
of  etiology  inadequate  which  fails  to  consider  the  aye  of  puberty,  the 
female  sc.r,  and  the  function  of  )iienstn(ation.  There  is  abundant  evi- 
dence to  show  that  heredity  also  is  an  important  factor,  as  the  disease 
is  often  observed  in  the  daughters  of  chlorotic  mothers,  while  a  tuber- 
culous family  history  has  been  remarkably  frequent  in  some  series  of 
cases.     (Trousseau,  Jolly,  Bramwell.) 

Great  importance  undoubtedly  attaches  to  general  lack  of  hygiene, 
especially  to  the  combination  of  poor  food  and  mental  depression. 
Stockman's  analyses  indicate  that  the  diet  of  chlorotic  girls  contains  as 
a  rule  too  little  iron. 

Considering  the  evidence  thus  briefly  reviewed,  the  writer  concludes 
that  chlorosis  is  a  specific  form  of  essential  anemia  which  results  from 
the  association  of  several  factors,  of  which  the  two  most  important  and 
invariably  present  are  (1)  a  predisposition  to  the  disease,  and  (2)  de- 
fective absorption  of  iron  from  the  food. 

The  predisposing  factors  are  most  pronounced  in  young  girls  at 
the  establishment  of  menstruation  when  the  unaccustomed  losses  of 
blood  and  the  peculiar  changes  in  the  nervous  system,  favor  the  ex- 


PLATE    [II. 


Mild  Chlorosis.     (Eosin  and  Methylene  Blue.) 


Fig.  I.  Slightly  deformed  red  cells,  with  enlarged  central  clear  areas,  indicating  loss  of  Hb. 

Fig.  2.  Poikilocyte. 

Figs.  3.  Normal  rouleaux. 

Fig.  4.  Medium-sized  lymphocyte. 

Fig.  5.  Polynuclear  neutrophile  leucocyte. 


CHANGES  IN   THE  BLOOD.  165 

pression  of  hereditary  tendencies  and  exaggerate  the  effects  of  bad 
hygiene,  and  when  additional  elements  are  thrown  in  the  balance,  such 
as  improper  food,  constipation,  gastroptosis,  mental  depression,  etc., 
the  blood  begins  to  suifer  in  a  peculiar  way  and  clinical  symptoms  are 
established  which  are  not  seen  in  secondary  anemias  occurring  in  the 
same  subjects.  The  essential  importance  of  the  absorption  of  iron  is 
indicated  by  its  specific  action,  but  it  seems  unnecessary  to  conclude,  as 
Stockman  has  done,  that  the  food  must  be  deficient  in  iron,  provided 
digestion  and  absorption  are  defective.  It  seems  to  be  an  invariable 
rule  that  chlorotics  do  not  recover  until  the  appetite  improves. 

The  exact  nature  of  the  pathogenic  process  in  the  disease  remains, 
however,  untouched  by  these  considerations,  and  it  still  remains  un- 
determined just  how  and  where  the  elaboration  of  Hb  is  disturbed, 
whether  in  the  intestinal  mucosa  (Garrod,  Forcheimer),  or  in  the  spleen 
(Kruger),  or  in  the  bone  marrow.  At  present  the  weight  of  evidence 
appears  to  be  almost  conclusive  that  chlorosis  results  from  a  functional 
insufficiency  of  the  bone  marrow,  brought  about  in  congenitally  pre- 
disposed subjects  by  a  series  of  conditions  most  often  combined  in 
young  women  at  puberty. 

Changes  in  the  Blood.  Specific  Gravity. — The  specific  gravity  of 
the  blood  in  chlorosis  is  reduced  in  very  uniform  ratio  with  the  loss  in 
Hb.  From  the  observations  of  Devoto,  Hammarschlag,  Schmaltz, 
Siegel,  Hock  and  Schlesinger,  Menicanti,  Stinzing,  and  Biernacki,  it 
has  been  shown  that  this  constant  relation  between  specific  gravity  and 
Hb-content  is  somewhat  peculiar  to  chlorosis.  It  is  most  uniform 
when  there  is  no  great  reduction  in  cells,  but  in  the  severer  types  of 
the  disease  the  ratio  is  less  constant. 

Jones  found  the  specific  gravity  of  the  blood  between  1.032-1.045 
in  87  cases,  while  that  of  the  serum  remained  nearly  normal,  1.0259 
-1.029.  These  results  were  verified  by  Hammarschlag  in  30  cases, 
in  which  the  blood  averaged  1.045,  the  serum  1.030.  The  reduction 
in  gravity  of  chlorosis  corresponds,  according  to  Jones,  to  a  physio- 
logical diminution  occurring  in  girls  at  puberty,  but  not  in  boys. 

The  bulk  of  blood  is  probably  not  altered  in  uncomplicated  chlorosis, 
although  Lloyd  Jones  considers  an  increase  in  the  volume  of  plasma 
to  be  a  very  constant  feature,  and  Stintzing  and  Gumprecht  believe 
that  oligemia  exists  in  some  peculiar  cases.  The  exuded  drop  is  pale 
in  proportion  to  the  anemia,  and  abnormally  fluid. 

The  Hemoglobin. — The  chief  alteration  in  the  blood  is  the  loss  of 
Hb  which  is  so  far  out  of  proportion  to  the  reduction  in  red  cells  that 
a  low  Hb-index  is  one  of  the  diagnostic  features  of  the  disease. 

A  contrary  opinion  is  held  by  Eichhorst  and  especially  by  Biernacki 
who,  finding,  as  did  also  Zumpf,  a  normal  or  increased  percentage  of 
iron  in  the  dried  residue  of  the  blood  in  some  cases,  believe  that  a  loss 
of  other  albumens  and  not  especially  of  Hb  is  the  essential  change  in  the 
disease.  The  basis  of  this  dissenting  opinion  will  be  further  consid- 
ered later. 

The  percentage  of  Hb  obtained  by  modern  instruments  has  been 


166  SPECIAL  PATHOLOGY  OF  THE  BLOOD. 

reported  as  low  as  10  (Bramwell) ;  but  when  the  Hb  falls  below  20 
percent  there  should  always  be  a  suspicion  of  some  complicated  or 
secondary  anemia. 

In  cases  of  average  severity  the  Hb  ranges  between  35-45  percent, 
and  the  Hb-index  about  .5.  Yet  some  authors  record  severe  cases 
with  high  Hb-index  (.80-.95,  Bramwell),  although  from  the  details  of 
these  reports  it  is  not  clear  to  what  this  variation  from  the  rule  is  re- 
ferable. These  cases,  in  the  writer's  experience,  fall  in  an  intermedi- 
ate group  between  chlorosis  and  pernicious  anemia  and  are  more  refrac- 
tory than  the  others.  Occasionally  the  Hb-index  is  very  low  (.20). 
(Bramwell.) 

v.  Noorden,'  from  extensive  observations,  finds  that  the  Hb-index 
is  apt  to  be  somewhat  higher  in  recurrent  than  in  initial  attacks,  but 
Romberg  could  not  verify  this  statement  in  a  group  of  relapsing  cases. 
The  writer  has  seen  illustrations  of  v.  Noorden's  rule  and,  since  in- 
crease in  size  of  cells  is  an  indication  of  chronicity  in  anemia,  believes 
that  the  observation  is,  in  general,  well  founded,  yet  as  Romberg 
states,  the  character  of  the  blood  changes  is  controlled  by  individual 
peculiarities  in  blood  formation  and  by  numerous  unhygienic  condi- 
tions. 

The  red  cells  are  in  most  cases  slightly  reduced,  although  almost 
invariably  much  less  affected  than  the  Hb.  Yet  not  infrequently  a 
considerable  grade  of  anemia  is  associated  with  a  normal  proportion  of 
red  cells.     A  high  count  of  red  cells  is  a  favorable  prognostic  sign. 

In  cases  of  average  severity  the  red  cells  run  from  3.5  to  four  mil- 
lions, while  in  severe  cases  the  number  falls  below  three  millions.  Ex- 
ceptional examples  in  which  less  than  two  million  cells  were  found  are 
recorded  by  Bramwell,  Cabot,  and  many  others,  while  Limbeck  records 
one  case  with  1,190,000,  and  Hayem  a  minimum  of  937,360.  In  such 
cases  the  Hb-index  is  often  comparatively  high. 

In  morphology  the  red  cells  present  characteristic  changes.  In  mild 
cases  and  those  of  average  severity,  the  sole  alteration  is  a  loss  of  Hb, 
which  causes  a  progressive  widening  of  the  central  clear  area  to  be  ob- 
served in  cells  rather  thickly  spread  and  slowly  dried.  In  all  well- 
marked  cases  the  appearance  of  such  blood  in  stained  smears  is  charac- 
teristic of  simple  anemia.  It  is  always  possible,  however,  to  find  a  few 
very  small  cells  and  some  extremely  deficient  in  Hb,  but  in  the  less 
severe  cases  these  features  are  not  pronounced.     (Plate  III.) 

When  chlorosis  is  of  long  standing  or  of  very  severe  grade,  with 
hydremic  plasma,  and  showing  a  tendency  to  relapse,  the  red  cells 
begin  to  exhibit  marked  variations  in  size  and  to  some  extent  also  in 
shape.  In  most  cases  in  which  the  response  to  iron  is  fairly  prompt 
these  changes  do  not  affect  any  considerable  proportion  of  cells.  In 
others  in  which  the  response  to  iron  is  less  certain  there  is  a  moderate 
number  of  large  cells  with  abundant  Hb.     (Plate  IV.) 

In  no  case  do  these  changes  reach  the  grade  seen  in  pernicious 
anemia,  but  in  a  group  of  cases  which  do  not  respond  well  to  iron  and 
are  apt  to  relapse  the  variations  in  size  of  the  cells  is  considerable,  and 


CHANGES  IN  THE  BLOOD.  167 

many  show  an  abundance  of  Hb.  On  the  other  hand  the  writer  has 
seen  persistently  relapsing  chlorosis  in  which  all  the  cells,  varying  con- 
siderably in  size,  were  very  deficient  in  Hb. 

PoikUocytosis  may  be  seen  in  all  severe  cases  of  chlorosis  but  is 
seldom  very  marked. 

Other  changes  occurring  with  moderate  frequency  in  the  red  cells 
of  chlorosis  are  the  polychromatic  degeneration  of  Maragliano  and  that 
of  Gabritschewsky.  Granular  degeneration  is  seen  to  a  slight  extent 
in  well-marked  cases. 

A  qualitative  change  in  the  Hb  in  chlorosis  is  suggested  by  the  re- 
sults of  Henrique's  experiments,  by  which  he  finds  that  oxyhemoglo- 
bin is  much  more  slowly  reduced  in  chlorosis  than  in  health  or  in  other 
forms  of  anemia. 

Nucleated  red  cells  are  seen  in  the  severer  cases  of  chlorosis 
under  various  conditions.  It  is  said  that  when  present  they  are  sub- 
ject to  periodical  variations  constituting  the  "  blood  crises."  (Neu- 
dorfer.)  Most  writers  have  found  them  too  scanty  even  in  severe 
cases  to  permit  a  full  verification  that  "  blood  crises  "  are  of  frequent 
occurrence,  and  this  common  experience  is  in  accord  with  the  theory 
that  functional  insufficiency  of  the  marrow  is  essentially  connected  with 
the  pathogenesis  of  the  disease.  Their  appearance  is  somewhat  favored 
by  rest  in  bed  and  large  doses  of  iron,  which,  as  Hoffman  has  shown, 
induce  hyperemia  and  cellular  hyperplasia  of  the  red  marrow.  The 
writer  has  seen  an  increased  number  during  the  leucocytosis  of  an  inter- 
current pneumonia. 

The  nucleated  red  cells  of  chlorosis  are  of  the  normoblastic  type,  and 
while  Neudorfer  and  Hammarschlag  report  finding  megaloblasts  in 
severe  relapsing  cases,  the  exact  nature  of  these  cases  is  not  entirely 
clear.     Their  observations  require  confirmation. 

Chemistry. — The  alkalinity  of  chlorotic  blood  has  been  found 
by  the  majority  of  investigators  to  vary  within  normal  limits  (Kraus, 
Steindler,  Limbeck)  or  in  some  cases  to  be  slightly  increased  (Graeber, 
Peiper,  Rumpf ).     v.  Jaksch,  however,  found  it  diminished. 

The  ISOTONIC  TENSION  of  the  red  cells  was  found  by  Limbeck  in 
two  cases  to  be  very  low,  .38-.4  percent  NaCl,  their  resistance  there- 
fore being  correspondingly  diminished. 

The  COAGULABILITY  of  chlorotic  blood  is  notably  greater  than  that 
of  other  forms  of  anemia  of  equal  grade,  a  rule  which  accords  with  the 
fact  of  the  preservation  of  the  albumens  of  the  plasma.     (Cf.  Biernacki.) 

The  PROPORTION  OF  WATER  in  chlorotic  blood  increases  from  the 
normal  (77  percent)  to  80-90  percent,  and  the  dry  residue  falls  from 
22-36  percent  to  19  percent,  with  60-70  percent  Hb,  or  as  low  as 
10.64  percent  of  residue  with  25  percent  Hb.  In  this  residue  the 
chlorides,  as  in  all  hydremic  states,  are  in  most  cases  considerably  in- 
creased. Phosphorus  is  moderately  reduced,  and  Fe  is  deficient  in  the 
well-marked  cases  only.  (Biernacki.)  When  the  Hb  is  below  70 
percent  the  reduction  in  Fe  is  rather  uniformly  proportionate  with  the 
loss  in  Hb. 


168 


SPECIAL  PATHOLOGY  OF  THE  BLOOD. 


Albumens. — Since  the  specific  gravity  of  the  serum  is  but  slightly 
altered  in  the  average  case  of  chlorosis,  the  loss  of  substance  must  af- 
fect principally  the  red  cells.  It  is  very  generally  agreed  that,  as 
shown  by  Becquerel  and  Rodier,  the  principle  chiefly  affected  is  the 
Hb,  but  Biernacki  found  a  normal  proportion  of  iron  in  the  dry  resi- 
due of  some  milder  cases  of  chlorosis  and  has  concluded  that  other 
albumenous  constituents  may  suifer  more  than  the  Hb.  In  Biernacki's 
analyses  of  more  severe  cases,  however,  a  marked  and  uniform  reduc- 
tion of  Fe  is  recorded. 

In  all  the  severer  cases  the  serum  is  poor  in  albumens,  but  markedly 
so  only  in  very  severe  cases.  The  hydremia  of  the  serum  in  chlorosis 
is  relatively  far  less  than  in  simple  anemia,  e.  g.,  post-hemorrhagic. 
(Grawitz.)  This  rule  is  found  by  Stintzing  and  Gumprecht  to  hold 
only  when  the  Hb  is  between  50-80  percent,  as  illustrated  in  the  fol- 
lowing table : 


Hb5«. 

21-30 

31-40 

41-50 

51-60 

61-70 

71-80 

81-85 

Dry 

Simple 
Anemia 

13.4  % 

12.0 

13.3 

14.5 

16.1 
18.3 

18.5 

Residue 

Chlorosis 

12.5 

13.4 

15.8 

18.8 

19. 

Regeneration  of  the  Blood  in  Chlorosis.     Red  Cells  and  Hb. — 

Hayem  divided  the  process  of  regeneration  of  the  blood  in  chlorosis 
into  two  periods,  one  in  which  the  red  cells  are  increased  in  number  by 
the  appearance  of  many  small  pale  and  deformed  cells,  followed  by  a 
second  in  which  these  new  cells  gradually  acquire  normal  characters. 
Similar  observations  have  been  made  by  the  majority  of  recent  ob- 
servers who  have  regarded  the  small  cells  seen  in  relative  excess  in 
well-marked  cases  as  being  recently  formed.  On  the  other  hand, 
Laache,  Stintzing  and  Gumprecht,  Reinert,  and  Graeber,  find  that  the 
increase  in  Hb  usually  outstrips  that  of  the  red  cells. 

More  recent  studies  in  this  field  have  thrown  some  light  on  the 
difficulty,  Romberg  showing  that  with  a  slight  decrease  of  cells  the  Hb 
increases  the  more  rapidly,  while  in  cases  with  marked  decrease  in  cells 
these  increase  first  and  more  rapidly  but  less  uniformly  than  the  Hb. 
In  some  severe  cases  Romberg  noted  a  slight  initial  diminution  in 
cells,  following  the  use  of  iron. 

Schaumann  and  Willebrand  have  recently  fully  demonstrated  that  in 
moderately  severe  cases,  under  iron,  there  is  a  progressive  increase  in 
the  average  diameter  of  the  red  cells,  resulting  from  the  disappearance 
of  undersized  corpuscles,  while  the  number  of  large  cells  becomes  con- 
siderable. The  authors  feel  justified  in  concluding  that  the  progress 
of  regeneration  is  not  marked  by  the  appearance  of  many  small  pale 
cells,  which  they  believe  are  degenerated  forms.  In  Romberg's  100 
cases,  in  all  of  which  the  cells  were  below  4  millions,  the  average 
duration  of  treatment  was  26.5  days,  the  Hb  increasing  9.9  percent 
and  the  red  cells  430,645  every  ten  days.  The  best  results  followed 
the  use  of  ferri  carb.  sac,  but  they  did  not  use  Bland's  pills. 


PLATE     IV 


Severe  Chlorosis.     (Eosiii  and   Methylene  Blue. 


g-  3 
g-4 
g-5 
g-6 

g-  7 


I.     Short  rouleau  of  cells  very  deficient  in   Hb. 
Medium-sized  megalocyte  deficient  in   Hb. 
Microcytes  deficient  in   Hb. 
Large  red  cell   with  central  droplet  of  Hb. 

Red  cell  with  central  basophilic  nuclear  remnant.     (Polychromasia  of  Maragliano.) 
Normoblast. 


Polynulcear    neutrophile     leucocyte,     over-stained    with    methylene    blue    and    showing 
basophilic  cytoreticulum. 


g.  8.     Blood  plates. 


VARIETIES  OF  CHLOROSIS.  169 

Distinct  polycythemia  has  in  many  instances  been  found  to  follow  re- 
covery from  chlorosis.  Schaumann  and  Willebrand  report  7.4  million 
cells  with  67  percent  Hb,  but  found  that  the  polycythemia  usually 
diminishes  as  the  Hb  reaches  a  normal  proportion.  In  some  severe 
cases,  on  the  other  hand,  it  seems  to  be  difficult  to  secure  complete  re- 
generation of  the  blood  and  the  anemia  relapses. 

An  increase  (12  pounds)  in  the  patient's  weight  without  correspond- 
ing increase  in  the  Hb  of  the  blood  cells,  but  with  increase  in  the 
solids  of  the  serum,  has  been  reported  by  Grawitz,  as  an  interesting 
feature  of  the  regeneration  of  the  blood  in  chlorosis.  A  moderate  in- 
crease in  the  number  of  nucleated  red  cells  and  of  leucocytes  is  some- 
times observed  in  cases  rapidly  recovering. 

Leucocytes. — The  leucocytes  in  the  average  case  of  chlorosis  show 
no  abnormal  variation  in  numbers  or  proportions.  (Graeber,  Grawitz.) 
The  average  in  239  cases  reported  by  Thayer,  Cabot,  and  Romberg, 
was  8,013.  Romberg's  tables  show  a  progressive  diminution  of  leu- 
cocytes as  the  anemia  grows  more  severe,  and  he  refers  this  rule  not  to 
any  absolute  decrease  in  the  number  of  cells  but  to  increase  in  the 
volume  of  plasma. 

Neusser  holds  that  some  less  favorable  types  of  chlorosis,  without 
regard  to  their  severity,  show  an  excess  of  lymphocytes  while  in  others 
the  presence  of  eosins  indicates  a  more  favorable  type  of  the  disease. 
In  the  latter  group  of  cases  Neusser's  pupils  found,  during  treatment 
with  iron,  a  slight  mixed  leucocytosis  in  which  the  proportions  of 
various  cells  are  normal. 

The  occurrence  of  myelocytes,  as  reported  by  Hammarschlag  and 
Neudorfer  is  very  unusual. 

Varieties  of  Chlorosis. — (a)  The  typical  examples  of  the  disease 
observed  in  young  w^omen  form  a  central  group  of  cases  which  has 
furnished  the  classical  and  accepted  picture  of  chlorosis.  The  blood 
in  these  cases  shows  a  low  Hb-index,  with  or  without  marked  loss  of 
cells.  They  run  an  acute  or  chronic  course  but  respond  well  to  iron. 
On  chemical  analysis  the  dry  residue  and  the  Fe  are  much  diminished 
and  the  symptoms  are  in  proportion  to  the  grade  of  anemia. 

Of  these  cases  one  may  distinguish  three  groups  of  somewhat  dif- 
ferent prognosis. 

1 .  The  red  cells  are  slightly  or  not  at  all  reduced  (about  4  millions) ; 
the  Hb-index  is  low  ;  there  are  no  changes  in  the  size  and  shape  of  the 
cells.  Such  patients  commonly  recover  very  promptly  and  the  anemia 
does  not  relapse. 

2.  The  red  cells  are  below  4  millions,  but  there  are  no  marked 
changes  in  the  shape  and  size  of  the  cells ;  the  Hb-index  is  very  low, 
the  patients  are  prostrated  but  with  iron  usually  recover  promptly,  and 
the  anemia  does  not  often  relapse. 

3.  The  red  cells  are  markedly  reduced  (below  3-3.5  millions) ;  there 
are  considerable  changes  in  shape  and  size,  the  Hb-index  varies,  but  is 
usually  very  low,  the  patients  respond  more  slowly  to  iron,  and  the 
anemia  often  relapses. 


170  SPECIAL  PATHOLOGY  OF  THE  BLOOD. 

(b)  A  group  of  cases  of  idiopathic  anemia  common  in  young  women 
has  long  been  recognized,  in  which  the  symptoms  resemble  those  of  re- 
fractory chlorosis,  but  which  in  some  other  respects  are  quite  different. 
Delafield  states  that  they  are  chiefly  distinguished  by  their  failure  to 
react  to  iron.  A  chronic  course  with  relapses  is  commonly  observed, 
but  a  change  to  distinct  pernicious  anemia  rarely  occurs.  The  blood 
of  such  subjects  shows  a  marked  reduction  in  red  cells,  commonly 
between  two  and  three  millions,  and  marked  variation  in  size  of  the 
cells,  a  considerable  number  of  which  have  increased  Hb.  The  Hb- 
index  may  be  very  low,  but  is  apt  to  be  higher  than  in  the  average 
case  of  chlorosis. 

It  is  possible  that  some  of  these  cases  are  much  more  anemic  than 
the  ordinary  blood-examination  indicates,  because  complicated  by  oligo- 
plasmia,  as  suggested  by  Lloyd  Jones  and  Biernacki. 

(c)  Pseudo-chlorosis  is  a  term  employed  by  various  recent  writers  to 
denote  a  group  of  cases  in  which  the  external  symptoms  of  chlorosis  are 
present  but  in  which,  from  the  examination  of  the  blood,  it  is  found 
that  the  Hb,  number  of  red  cells,  percentage  of  dry  residue,  and  usu- 
ally the  proportion  of  iron,  are  nearly  normal.  Several  explanations 
nave  been  offered  regarding  these  obscure  cases. 

Lloyd  Jones  believes  that  they  are  cases  of  anemia  with  oUgoplas- 
mia,  in  which  the  real  deficiency  of  Hb  and  cells  is  masked  by  dimi- 
nution in  the  quantity  of  plasma.  He  offers  no  chemical  analyses  to 
support  his  view.  Biernacki  has  studied  this  condition  in  detail  and 
as  a  result  of  clinical  observations  and  chemical  analyses,  he  concludes 
that  in  cases  of  anemia  there  is  a  condition  of  oligoplasmia  with 
hydremia  of  both  cells  and  plasma,  so  that  while  the  blood  shows 
normal  Hb,  yet  the  swollen  cells  are  deficient  in  this  principle,  and 
both  cells  and  plasma  are  deficient  in  albumens.  In  short,  Biernacki 
claims  to  have  demonstrated  that  it  is  possible  to  have  hydremic  blood 
which  yet  gives  a  normal  percentage  of  Hb  and  a  normal  number  of  red 
cells.  Biernacki  points  out  that  two  of  the  eight  original  cases  ex- 
amined by  Becquerel  and  Rodier,  and  two  cases  reported  by  Stintzing 
and  Gumprecht  showed  slight  hydremia,  a  nearly  normal  percentage 
of  Fe,  but  well-marked  symptoms  of  chlorosis.  He  protests  against 
calling  such  cases  pseudo-chlorosis,  believing  that  they  are  genuine 
examples  of  the  disease,  and  claims  that  the  essential  element  in  chlo- 
rosis is  not  the  loss  of  Hb  and  Fe,  but  that  the  disease  is  a  neurosis 
with  hydremia,  and  with  or  tvithout  loss  of  Fe. 

If  Biernacki's  results  obtain  confirmation,  which  they  have  not  yet 
secured,  much  needed  light  may  be  thrown  upon  a  large  group  of 
cases  in  which  the  symptoms  of  anemia  are  associated  with  apparently 
normal  blood.  Such  cases  occur  usually  in  young  women,  are  often 
encountered  in  gynecological  clinics  because  of  amenorrhea,  and  have 
been  fully  described  especially  by  Biernacki,  and  Romberg.  It  is 
possible,  also,  that  a  similar  explanation  may  apply  to  the  cases  of 
pseudo-chlorosis  described  by  Stintzing  and  Gumprecht  and  others, 
and  very  commonly  encountered  in  tuberculous  subjects. 


BIBLIOGRAPHY.  171 

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Bihler.     Deut.  Archiv  klin.  Med.,  Bd.  52,  p.  281. 

Bouchard.     Lecons  sur  1' autointoxication,  Paris,  1887. 

Bramwell.     Anaemia,  etc.,  p.  22. 

Bunge.     Verb.  XIII.  Cong.  inn.  Med.,  1895. 

Chvostek.     Wien.  klin.  Woch.,  189,3,  p.  487. 

Clark.     Lancet,  1887,  II. ,  p.  1003. 

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Duncan.     Sitzungsber.  d.  Wien.  Acad.,  1867. 

Eichhorst.     Cited  by  v.  Noorden. 

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Forcheimer.     Amer.  .Jour.  Med.  Sci.,  Vol.  106. 

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Garrod.     Archiv  of  Path,  and  Bact.,  1892,  I.,  p.  195. 

Graeber.  Therapeut.  Monatsbefte,  1887,  p.  380.  Arb.  a.  d.  med.-klin.  Institut 
Miinchen,  Leipsic,  1890. 

Gram.     Fort.  d.  Med.,  1884,  p.  33. 

Grawitz.     Klin.  Pathol.,  p.  76. 

Hammarschlag.    Zeit.  f.  klin.  Med.,  Bd.  21,  p.  475.  Wien.  med.  Presse,  1894,  p.  1068. 

Hay  em.     Du  sang.,  p.  619. 

Hock,  Schlesinger.     Beitriige  znr  Kinderheilk.,  II.,  N.  F.,  1892. 

Hoffman.     Lehrb.  d.  Constitutionskrank.,  1893.     Miinch.  med.  Woch.,  1899,  p.  949. 

V.  'Hosslin.     Miinch.  med.  Woch.,  1890,  p.  248. 

V.  Jaksch.     Prager  med.  Woch.,  1890,  No.  31. 

Jolly.     Influence  d.  tuberc.  sur  Chlorose,  Paris,  1890. 

Jones.     Chlorosis,  London,  1897,  p.  23. 

Kraus.     Zeit.  f.  Heilk.,  Bd.  10. 

Kruger.     St.  Petersburg  med.  Woch.,  1892,  p.  471. 

Laaehe.  Die  Anaemic,  1883,  p.  81.  Cited  in  Hoffman's  Lehrbuch  d.  Constitutions- 
krank., Stuttgart,  1893. 

Lipman,  Wulf.  Ueber  Eiweisszersetzung  bei  Chlorose,  Berlin,  1892.  Cited  by 
V.  Noorden. 

Lichtenslern.     Untersuch.  u.  d.  Hemoglobingehalt  d.  Blut.,  1878. 

Limbeck.     Grundriss,  etc.,  p.  305. 

Luton.     Bull.  Soc.  med.  Rheims,  No.  10. 

Meincrt.     Samml.  klin.  Vortriige,  1895. 

Menicanti.     Deut.  Archiv  klin.  Med.,  Bd.  50,  p.  407. 

Morner.     Zeit.  f.  physiol.  Chem.,  1893,  XXIII. 

Murri.     Semaine  Med.,  1894,  162. 

Neudorfer.     Wien.  med.  Presse,  1894,  p.  1068. 

V.  Noorden.  '  Chlorose  Wien. ,  1897.  ^Berl.  klin.  Woch.,  1895,  p.  181.  ^ibid., 
1894,  p.  786. 

Nothnagel.     Wien.  med.  Presse,  1891,  No.  51. 

Ortner.     Wien.  klin.  Woch.,  1891,  p.  2. 

PaltauJ.     Wien.  klin.  Woch.,  1889,  p.  877  ;  1890,  p.  172. 

Peiper.     Cent.  f.  inn.  Med.,  1891,  No.  12. 

Pick.     Wien.  klin.  Woch.,  1891,  p.  939. 

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Romberg.     Berl.  klin.  Woch.,  1897,  p.  533. 

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Zumpf.     Inaug.  Diss.  Dorpat,  1891. 


CHAPTER    VII. 

PROGRESSIVE   PERNICIOUS   ANEMIA. 

This  term  is  applied  to  a  peculiar  group  of  diseases  of  the  blood  re- 
sulting from  defective  hematogenesis  and  excessive  hematolysis,  charac- 
terized by  severe  and  usually  fatal  anemia,  peculiar  morphological 
changes  in  the  red  cells,  and  by  characteristic  changes  in  the  bone 
marrow.  Although  excited  by  a  number  of  well-recognized  conditions, 
progressive  pernicious  anemia  differs  from  secondary  anemia  in  the 
peculiar  changes  in  the  red  cells,  in  the  lesions  of  the  marrow,  in  its 
tendency  when  once  established  to  progress  to  a  fatal  issue,  and  in  the 
fact  that  the  anemia  is  apparently  out  of  proportion  to  the  exciting 
cause,  while  very  often  no  cause  whatever  can  be  assigned. 

The  disease  has  often  been  described  as  primary  pernicious  anemia, 
but  since  typical  examples  have  been  positively  traced  to  the  effects  of 
intestinal  parasites,  it  becomes  necessary  to  admit  that  this  condition  of 
the  blood  is  not  always  of  cryptogenic  origin.  Nevertheless  its  patho- 
logical features  remain  so  distinctive  as  to  justify  the  common  belief  in 
the  peculiar  nature  of  the  disease. 

Hldorlcal. — A  review  of  the  early  literature  on  pernicious  anemia, 
as  collected  by  Eichhorst,  Musser,  and  Stockman,  shows  that  while  the 
disease  had  previously  been  described  by  observers  in  many  countries 
its  symptomatology,  gross  pathology,  and  separation  from  chlorosis  and 
secondary  anemia,  were  not  clearly  stated  until  Addison  in  1855  pub- 
lished the  description  of  cases  observed  by  him  clinically  and  examined 
at  autopsy  during  the  previous  decade. 

Of  the  earlier  reported  cases  those  of  Andral  (1821)  in  France,  of 
Coombe  (1823)  and  Hall  (1843)  in  England,  and  of  Channing  (1849) 
in  America,  were  so  clearly  described  as  to  leave  no  doubt  that  fatal 
idiopathic  anemia  was  fully  recognized  by  some  observers  at  that  early 
time.  Channing,  and  other  Boston  physicians,  had  notes  on  such  cases 
as  early  as  1832,  and  his  descriptions  of  cases  in  1849  were  sufficiently 
complete  to  warrant  their  acceptance  as  referring  to  genuine  examples 
of  the  disease. 

Lebert  in  Zurich  had  apparently  recognized  and  partially  described 
the  disease  as  early  as  1854,  but  his  pathological  reports  were  too  scanty 
to  demonstrate  the  probable  specific  nature  of  the  malady  which  he 
did  not  claim  till  1858,  although  recognizing  it  as  a  fatal  form  of 
anemia.  Long  before  this,  as  shown  by  Lepine,  some  prominent  text- 
books had  called  attention  to  the  occurrence  of  fatal  cases  of  anemia, 
considering  them  usually  as  instances  of  fatal  chlorosis.  (Piorry, 
Wunderlich,  Schonlein,  Rokitansky,  Canstatt.) 


PROGRESSIVE  PERNICIOUS  ANEMIA.  173 

Addison,  however,  offered  more  abundant  clinical  and  pathological 
evidence  to  show  that  the  disease  is  of  idiopathic  origin,  fully  distin- 
guishable from  secondary  anemia,  but  he  supposed  that  the  fatty 
changes  were  the  cause  not  the  result  of  the  anemia.  In  1857  Wilks' 
description  of  seven  cases  was  very  clear  and  indicates  that  the  condition 
had  then  become  well  identified  at  Guy's  Hospital  and  was  distin- 
guished from  secondary  anemia  and,  by  the  examination  of  the  blood, 
from  leukemia. 

In  Germany  there  were  fragmentary  reports  of  probable  cases  by 
Zenker,  1856;  Wagner,  1859;  and  Grohe,  1861  ;  until  Biermer  in 
1868  collected  a  series  of  cases  observed  in  Zurich  during  previous 
years  and  gave  such  a  systematic  description  of  the  clinical  symptoms 
as  to  attract  general  attention  to  the  malady  as  a  special  form  of  anemia. 
Biermer  failed  to  add  to  the  knowledge  of  the  pathology  of  the  disease 
and  paid  little  attention  to  the  blood  and  when  Immerman  contributed 
important  critical  studies  in  1874-1877,  interest  in  the  microscopical 
examination  of  the  blood  concerned  chiefly  the  proportion  of  leucocytes. 

The  early  observers,  especially  Wilks,  had  noted  the  marked  olige- 
mia, hydremia,  and  feeble  coagulation  of  the  blood  at  autopsy,  and  by 
microscopical  examination  during  life  had  demonstrated  an  excessive 
loss  of  red  cells  and  a  small  proportion  of  leucocytes,  but  for  many 
years  no  further  advance  was  attempted  in  this  field.  In  1873  Pon- 
fick  found  a  relative  increase  of  leucocytes  in  one  case,  probably  from 
ante-mortem  leucocytosis,  and  noted  a  greenish  tinge  of  the  serum. 

In  1876  Quincke  described  the  appearance  of  microcytes  and  poiki- 
locytes  in  several  cases,  while  Eichhorst,  at  the  same  time,  noted  the 
absence  of  rouleaux  and  the  increase  of  Hb  in  some  microcytes,  cells 
which  he  regarded  as  pathognomonic  of  the  disease. 

By  this  time  Bizzozero's  and  Neumann's  demonstration  of  the 
function  of  the  bone  marrow  in  blood  formation  began  to  turn  atten- 
tion to  this  tissue.  Pepper  (with  Tyson)  making  the  first  contributions 
in  a  new  field  in  1875.  Pepper  found  uncertain  evidences  of  a  cellu- 
lar hyperplasia  in  some  portions  of  the  marrow,  that  of  the  radius 
appearing  paler  than  normal  while  that  of  the  sternum  was  quite  red. 

A  great  advance  was  made  when  Cohnheim  in  1876  presented  a 
brief  communication  on  the  changes  in  the  bone  marrow  in  a  case  of 
pernicious  anemia.  He  reported  finding  an  unusual  hyperplasia  of 
the  red  marrow  with  complete  atrophy  of  fat  cells,  increase  of  myelo- 
cytes, large  and  small,  absence  of  normal  red  cells  and  the  presence 
of  megalocytes,  microcytes,  and  large  numbers  of  megaloblasts.  In 
the  blood  of  the  vena  cava  he  found  a  few  large  nucleated  red  cells 
but  had  failed  to  find  them  in  the  peripheral  blood  during  life.  Cohn- 
heim expressed  the  opinion  that  the  essential  element  in  the  malady 
was  a  primary  disease  of  the  marrow  affecting  the  development  of  the 
red  corpuscles,  leading  to  production  of  megalocytes  at  the  expense  of 
smaller  properly  functionating  cells,  the  whole  constituting  a  reversion 
to  the  embryonal  type  of  blood  formation.  Cohnheim  thus  completed  the 
chain  of  pathological  evidence  that  was  required  to  establish   the  dis- 


174  PROGRESSIVE  PERNICIOUS  ANEMIA. 

tinctive  nature  of  the  disease,  and  demonstrated  the  importance  of 
closer  study  of  the  blood  as  the  seat  of  the  primary  lesion.  The  fur- 
ther study  of  the  marrow  was  taken  up  by  Osier  and  Gardner,  Neu- 
mann, Litten  and  Orth,  P.  Grawitz,-  and  many  others,  whose  results 
have  shown  that  the  study  of  the  changes  in  the  marrow  gives  the 
deepest  insight  into  the  essential  process  of  the  disease. 

The  first  enumeration  of  red  cells  was  reported  by  Sorensen,  who, 
using  Malassez's  method,  found  in  one  case  only  470,000  cells ;  by 
Lepine  ^  who,  with  Hayem's  method,  reported  a  reduction  to  909,000- 
378,750,  and  by  Ferrand  who  found  500,000  red  cells  and  10  per- 
cent of  Hb.  Of  morphological  changes  an  increase  in  size  of  the  red 
cells  during  the  course  of  the  disease  was  noted  by  Lepine  ;  a  slight 
brownish  tinge  by  Strieker ;  the  presence  of  ameboid  processes  by 
Scheby-Buch ;  the  oval  form  and  absence  of  rouleaux  by  Bradbury. 
In  1876  Quincke  described  the  appearance  of  microcytes  and  poikilo- 
cytes  in  several  cases.  Eichhorst  (1878)  found  the  most  striking  char- 
acteristics to  be  the  large  size,  pallor,  and  scarcity  of  the  red  cells. 
Yet  all  these  characteristics  Eichhorst  had  seen  in  a  case  of  gastric 
cancer,  whence  he  maintained  that  the  blood  of  pernicious  anemia 
showed  no  single  pathognomonic  sign.  While  Quincke  had  observed 
that  many  microcytes  seemed  to  contain  an  excess  of  Hb  and  that  the 
blood  of  pernicious  anemia  was  more  highly  colored  than  the  number 
of  red  cells  warranted,  it  was  Hayem  ^  who  first  demonstrated  that  an 
increased  Hb-index  is  characteristic  of  the  disease,  while  Laache  showed 
this  feature  to  be  referable  to  the  presence  of  many  megalocytes  with 
increased  Hb. 

By  1880  there  were  only  two  reported  cases  in  which  nucleated  red 
cells  had  been  found  during  life,  when  Ehrlich,  examining  stained  dry 
preparations  claimed  that  while  nucleated  red  cells  were  found  in  all 
cases  of  severe  anemia,  megaloblasts  were  seen  exclusively  in  progres- 
sive pernicious  anemia.  Only  in  recent  years  has  this  claim  been 
shown  to  be  but  partially  valid.  In  1891  Luzet  first  reported  the 
discovery  of  mitotic  nuclei  in  megaloblasts  from  the  blood  of  a  child,  the 
occurrence  of  which  has  since  been  shown  to  be  a  nearly  pathogno- 
monic sign  of  the  disease  in  adults.  With  the  observations  on  poly- 
chromatic degenerative  changes  in  red  cells  these  lesions  were  found  to 
be  specially  distinct  in  pernicious  anemia.  In  one  of  v.  Noorden's 
dissertations  was  first  mentioned  the  occurrence  of  basic  staining  gran- 
ules in  the  bodies  of  megalocytes,  which  was  later  verified  by  Askanazy 
and  interpreted  as  evidence  of  karyorhexis. 

The  contributions  on  etiology  which  have  steadily  accumulated  from 
many  sources,  and  the  progress  of  the  knowledge  of  the  chemistry  of 
the  blood,  chiefly  through  the  work  of  v.  Jaksch,  Grawitz,  Dieballa, 
et  al.,  will  be  considered  under  those  topics. 

General  Etiology. — After  the  demonstration  of  striking  and  pecu- 
liar changes  in  the  blood  and  marrow  it  was  generally  accepted  that 
progressive  pernicious  anemia  is  of  idiopathic  origin,  although  Biermer 
enumerated  a  list  of  exciting  causes  which  appeared  to  have  been  present 


SCOPE  OF  TERM  PROGRESSIVE  PERNICIOUS  ANEMIA.       175 

in  his  cases,  viz,  insufficient  food,  bad  hygiene,  prolonged  diarrhea,  re- 
peated hemorrhages.  Yet  it  appeared  that  the  assignable  causes  were 
inadequate  to  account  for  the  result  and  it  was  felt  that  the  disease 
could  in  no  respect  be  classed  with  the  ordinary  cases  of  secondary 
anemia  such  as  follow  carcinoma,  nephritis,  hemorrhages,  etc. 

The  first  retrenchment  of  this  view  was  rendered  necessary  by  the 
discovery  of  typical  cases  of  the  disease  referable  to  the  presence  of  in- 
testinal parasites  (Bofhriocephalus)  and  which  recovered  promptly  after 
expulsion  of  the  worms.  These  cases  showed  that  there  is  not  neces- 
sarily any  cryptogenic  factor  in  the  etiology  of  the  disease,  and  that 
the  presence  of  the  typical  blood  changes  does  not  necessarily  imply  a 
fatal  course  of  the  anemia.  Likewise  the  changes  in  the  marrow  were, 
for  a  time,  robbed  of  much  of  their  pathognomonic  value  by  the  report 
that  very  similar  changes  are  established  in  some  cases  of  multiple 
hemorrhages  (Neumann),  tuberculosis  (Litten),  and  gastric  cancer 
(Eisenlohr).  Further,  the  changes  in  the  blood  have  now  been  shown 
to  follow  syphilis  (F.  Muller  ^),  ^malaria  (Bignami,^  the  writer) ;  atrophy 
of  gastro-intestinal  mucosa  (Fenwick,  Brabazon,  Henry,  Osier,  Noth- 
nagel,  Stengel) ;  typhoid  fever  (Quincke,  Rosenstein,  P.  Grawitz) ;  pro- 
longed diarrhea  (Wilks,  Frankel,  Strieker) ;  myeloid  sarcoma  (Litten) ; 
in  each  of  which  conditions  it  is  occasionally  impossible  to  say  that  the 
cause  is  inadequate  to  the  result,  and  there  remain  only  the  acute  cases 
without  demonstrable  origin  but  referred  by  some  to  intestinal  auto- 
intoxication, and  the  cases  that  follow  pregnancy,  which  can  still  be 
held  as  of  cryptogenic  nature. 

Scope  of  the  Term  Progressive  Pernicious  Anemia. — In  view  of 
this  present  state  of  the  subject  two  plans  of  classification  of  the  severe 
anemias  of  the  Addison-Biermer  type  have  been  suggested  by  Birch- 
Hirschfeld  and  Grawitz. 

Birch-Hirschfeld  claims  that  there  is  no  good  reason  to  separate  on 
etiological  grounds  alone  cases  of  severe  anemia  of  cryptogenic  origin  from 
those  like  the  anemia  of  bothriocephalus,  in  which  an  adequate  cause  is  ap- 
parent. For  both  show  the  same  anatomical  evidence  to  prove  that  the 
pathological  process  in  each  is  identical.  He  would,  therefore,  class  together 
all  severe  anemic  conditions,  without  regard  to  origin,  in  which  there  is  de- 
generation and  loss  of  red  cells,  increased  destruction  of  tissue-albumeus, 
and  fatty  changes  in  the  viscera,  and  in  which  the  chief  factors  are  excessive 
destruction  and  defective  formation  of  red  cells. 

Against  this  proposition  Grawitz  urges  that  it  is  clinically  inapplicable, 
because  fatty  changes  in  viscera  can  be  recognized  only  after  death,  that  it 
classes  together  anemias  arising  from  such  diverse  causes  as  cancer,  malaria, 
sepsis,  anchylostomiasis,  etc.,  and  that  increased  destruction  of  albumens 
is  not  a  constant  feature  of  the  disease,  although  present  in  some  forms  of 
milder  secondary  anemia.  Grawitz  therefore  proposes  to  throw  out  of  the 
category  of  progressive  pernicious  anemia  those  cases  in  wliich  the  etiology 
is  known,  e.  g.,  bothriocephalus,  and  to  retain  in  this  class  only  those  cases 
in  which  the  most  thorough  examination  of  the  patient  fails  to  show  any 
primary  disease. 

This  suggestion  accords  with  the  view  of  those  who  fail  to  see  in  the  his- 
tological changes  in  blood  and  marrow,  evidence  of  a  peculiar  condition  in- 
terpreted by  Cohnheim,  Ehrlich,  and  many  others,  as  a  reversion  to  the 
embryonal  type  of  blood  formation. 


176  PROGRESSIVE  PERNICIOUS  ANEMIA. 

The  writer,  having  failed  to  find  from  any  source  a  controversion  of 
the  view  that  the  changes  in  the  blood  and  marrow  described  in  per- 
nicious anemia  result  from  a  peculiar  patliological  process  which  is  es- 
sentially different  from  that  seen  in  the  majority  of  secondary  anemias, 
must  accept  the  opinion  that  when  the  blood  contains  megaloblasts  and 
a  considerable  proportion  of  megalocytes  with  increased  Hb,  while  the 
lymphoid  marrow  shows  marked  hyperplasia  of  peculiar  type,  the  con- 
dition should  be  called  progressive  pernicious  anemia,  without  regard 
to  its  immediate  exciting  cause.  The  essential  process  in  the  disease 
is  a  reversion  of  the  marrow  to  a  type  of  blood  formation  which  in 
some  respects  resembles  the  embryonal,  and  it  would  seem  to  make 
very  little  difference  how  various  the  exciting  agents  may  be,  whether 
sypliilis,  malaria,  anchylostomiasis,  or  intestinal  auto-intoxication,  pro- 
vided they  all  initiate  the  same  process  and  stamp  the  anemia  with 
certain  self-perpetuating  tendencies  not  seen  in  other  conditions. 

Special  Etiology. — Progressive  pernicious  anemia  is,  as  shown  by 
its  history,  a  disease  of  very  general  distribution  and  comparatively 
frequent  occurrence.  In  the  Berlin  City  Hospital,  Lazarus  found  274 
cases  recorded  in  10  years,  or  2  percent  of  the  admissions.  It  is  con- 
siderably less  common  in  New  York  hospitals,  but  consultants  in  the 
city  see  from  6-12  cases  yearly. 

The  female  sex  is  considerably  more  subject  to  the  disease  than  are 
males,  owing  probably  to  the  predisposing  influence  of  pregnancy. 
(MuUer,  Ehrlich.) 

The  240  reported  cases  collected  by  Ehrlich  were  distributed  be- 
tween the  ages  as  follows  : 

1-10 1  case 

10-20 22  cases 

20-30 ()1     " 

30-40 67     " 

40-50 47     " 

50-60 33     " 

60-70 7     " 

70-80 2     " 

Monti  and  Bergrun  collected  16  cases  in  children,  of  which  5 
occurred  between  the  first  and  fifth  years,  and  9  between  the  fifth  and 
fourteenth  years.  Ehrlich  hesitated  to  accept  these  as  genuine  cases 
on  account  of  the  uncertain  significance  of  changes  in  the  blood  in  early 
life. 

Bothriocephalus  Anemia. — The  first  important  inroad  made  upon  the 
group  of  idiopathic  pernicious  anemia  was  accomplished  when  Hoffman 
in  1885,  followed  by  Botkin,  Reyher,  and  Runeberg,  showed  that  the 
presence  in  the  intestine  of  many  of  these  worms  often  leads  to  a  severe 
or  fatal  anemia  which  may  be  made  to  disappear  by  the  expulsion  of 
the  worms.  While  Reyher  and  Runeberg  in  1886,  and  F.  Muller  in 
1889,  claimed  that  the  morphology  of  the  blood  in  these  severe  cases  is 
identical  Avith  that  of  primary  pernicious  anemia,  from  the  presence  of 
megalocytes  with  increased  Hb,  megaloblasts,  etc.,  the  complete  iden- 
tity of  the  condition  existing  in  fatal  cases  with  that  of  progressive  per- 


SPECIAL  ETIOLOGY.  Ill 

nicious  anemia  was  fully  established  by  Schaumann's  extensive  studies 
in  the  same  locality.  It  is  of  great  interest  that  in  some  of  Schaumann's 
cases,  although  the  reduction  of  cells  and  Hb  was  not  marked,  yet 
Ehrlich's  signs  of  progressive  pernicious  anemia,  megalocytes  with  in- 
creased Hb  and  megaloblasts,  were  abundantly  present.  In  Askanazy's 
cases"  normoblasts  were  found  in  small  numbers  among  many  megalo- 
blasts, the  former  rapidly  replacing  the  latter  as  the  anemia  improved. 

While  the  fact  that  the  worms  cause  the  anemia  seems  to  be  proved 
by  the  rapid  recovery  observed  in  some  cases  following  their  expulsion 
(Wiltschur,  Askanazy),  no  satisfactory  explanation  of  the  pathogenic 
action  of  the  parasites  has  been  obtained.  It  appears  that  large  num- 
bers of  worms  are  required  to  produce  the  severe  anemias,  as  many  as 
100  having  been  expelled  from  a  patient  of  Boetticher's,  although  in 
other  instances  the  usual  small  number  was  found.  The  duration  of 
the  infection  appears  to  exert  little  influence,  as  is  evident  from  the 
cases  reviewed  by  Askanazy.  (The  writer  secured  4  full-grown  speci- 
mens from  a  healthy  Swede  who  had  been  in  America  for  1 7  years. ) 
Schapiro  and  Dehio,  finding  some  dead  parasites  in  their  cases,  con- 
cluded that  only  the  decomposing  iconn  produces  the  specific  toxine  which 
causes  the  anemia,  but  the  majority  of  parasites  found  in  severe  cases 
are  living.  Wiltschur  followed  this  clue  further,  finding  that  the 
majority  of  parasites  were  dead,  and  decomposing,  or,  as  he  concluded 
from  alterations  in  the  eggs,  "  sick."  Some  cases  (Schaumann,  Neu- 
bucher)  in  which  anemia  was  present  while  no  parasites  but  only  eggs 
were  found  in  the  intestines  at  autopsy,  Ehrlich  believes  can  be  ex- 
plained as  resulting  from  the  complete  absorption  of  recent  decayed 
parasites.  This  reasoning  it  is  difficult  to  follow,  nor  can  great  im- 
portance be  attached  to  the  results  of  Schaumann  and  Tallquist  who  in 
the  course  of  two  weeks  considerably  reduced  the  red  cells  of  a  dog  by 
injections  of  a  glycerine  extract  of  the  crushed  bodies  of  the  worms. 

At  present  therefore  it  seems  impossible  to  reach  any  satisfactory 
explanation  why  this  parasite  should  behave  at  times  as  a  harmless 
denizen  of  the  intestinal  tract,  but  at  others  should,  apparently,  destroy 
its  host  through  a  fatal  anemia. 

The  occurrence  of  fatal  anemia  referable  to  the  presence  of  other  in- 
testinal parasites,  especially  Anchylostoma  duodenale,  was  demonstrated 
by  Griesinger  in  1851  and  has  been  fully  corroborated  by  Perroncito, 
Leichenstern,  Sand  with,  etc.  While  it  appears  very  probable  that  the 
same  blood  changes  are  established  in  these  cases  as  by  infection  with 
bothriocephalus,  there  appear  to  be  no  detailed  studies  of  the  blood  and 
marrow  which  can  fully  support  such  a  view.  Indeed,  Zappert  in  a 
few  cases  of  considerable  severity  found  the  ordinary  characteristics  of 
secondary  anemia,  and  a  low  Hb-index,  but  did  not  apparently  con- 
sider the  morphological  changes  in  the  red  cells.  In  Sandwith's  re- 
markable experience,  although  the  red  cells  were  sometimes  reduced 
below  a  million,  the  Hb-index  was  usually  low,  the  clinical  symptoms 
and  pathological  lesions  were  not  distinctive  of  progressive  anemia, 
while  there  is  no  report  of  morphological  examination  of  the  blood. 
12 


178  PROGRESSIVE  PERNICIOUS  ANEMIA. 

The  report  of  Demme  of  two  cases  of  fatal  anemia  in  children  in 
whose  intestines  large  numbers  of  Asearides  were  found,  is  of  interest 
but  too  isolated  to  be  of  great  importance. 

Repeated  Hemorrhages. — That  genuine  progressive  pernicious  anemia 
may  follow  repeated  hemorrhages  has  been  claimed  by  many  observers 
who  have  not  insisted  upon  Ehrlich's  signs  in  their  diagnoses.  (Ha- 
bershon,  Quincke,  Scheperlen,  Finney,  Greenhow,  Stockman.)  In 
recent  years  reports  of  genuine  cases  of  this  origin  have  not  been  so 
numerous,  yet  Ehrlich  and  Lazarus  accept  as  a  fact  their  frequent  oc- 
currence from  this  cause.  The  writer  has  not  seen  any  cases  directly 
referable  to  hemorrhage. 

It  is  probable  that  the  genuine  cases  observed  after  pregnancy  are 
partly  the  result  of  the  losses  of  blood  during  and  after  parturition. 
Stockman  goes  so  far  as  to  urge  that  all  cases  now  called  idiopathic  are 
the  result  of  repeated  minute  intestinal  hemorrhages,  in  which  opinion 
he  stands  unsupported. 

While  granting  as  does  Ehrlich  that  the  disease  occasionally  follows 
repeated  hemorrhages,  it  still  remains  true  that  the  great  majority  of 
chronic  post-hemorrhagic  anemias  follow  the  type  of  secondary  anemia 
with  very  low  Hb-index,  and  w'ith  leucocytosis. 

Pregnancy  was  one  of  the  conditions  first  recognized  as  a  prominent 
exciting  cause  of  pernicious  anemia,  the  most  numerous  cases  (29) 
(35  percent)  of  those  collected  by  Eichhorst  (1878)  coming  under 
this  heading. 

The  genuineness  of  some  of  these  cases  may  now  be  doubted,  and 
at  any  rate  the  patients  suffered  from  a  variety  of  severe  symptoms 
not  at  present  regarded  as  belonging  to  the  disease,  so  that  Lazarus 
classes  many  of  them  as  examples  of  secondary  anemia  and  exhaustion. 
In  others,  however,  the  pregnancy  was  uneventful  except  for  the  spon- 
taneous development  of  severe  anemia  ending  fatally  before  or  after 
parturition,  so  that  Lebert  ascribed  to  pregnancy  a  special  nervous  in- 
fluence leading  to  fatal  anemia,  and  Birch-Hirschfeld  assumed  that 
placental  toxines  affect  first  the  plasma  and  later  the  red  cells.  These 
theoretical  considerations  have  been  rendered  unnecessary  by  the  grad- 
ual disappearance  from  literature  of  cases  of  progressive  anemia  fol- 
lowing pregnancy.  Ehrlich  could  find  only  one  case  of  this  description 
in  recent  literature  (Laache,  Case  9).  At  Sloane  Maternity  Hos- 
pital from  1892—1899  the  writer  saw  many  cases  of  severe  anemia, 
but  none  of  the  progressive  pernicious  type.  Ahlfeld,  in  a  wide 
experience,  could  not  report  a  single  case  following  pregnancy, 
(1898).  The  rather  numerous  current  reports  of  severe  anemia  fol- 
lowing pregnancy  refer  to  a  severe  secondary  type,  and,  as  Ehrlich 
concludes,  it  is  impossible  to  ascribe  to  pregnancy  any  peculiar  influ- 
ence in  the  origin  of  the  disease. 

Syphilis. — That  syphilis  is  occasionally  followed  by  anemia  in  which 
the  morphological  changes  in  the  blood  are  identical  with  those  of  pro- 
gressive pernicious  anemia,  seems  to  be  fairly  well  attested  by  the  re- 
ported cases  of  Laache,  Kjerner,  and  F.  Muller. 


SPECIAL  ETIOLOGY.  179 

In  children  suffering  from  hereditary  syphilis  the  variations  in  the 
size  of  red  cells,  their  increase  of  Hb,  and  the  large  numbers  of 
megaloblasts,  seem  to  leave  little  doubt  that,  in  this  age  at  least, 
syphilis  figures  as  an  exciting  cause  of  progressive  pernicious  anemia. 
(Loos,  Luzet.)  Yet  the  reports  in  recent  literature  have  not  strength- 
ened the  view  that  syphilis  may  lead  directly  to  this  peculiar  type  of 
anemia.  The  changes  in  the  blood  seen  in  the  great  majority  of  cases, 
•iilthough  often  severe,  seem  to  follow  the  type  of  simple  secondary 
anemia.  Consequently  Ehrlich  and  Lazarus  doubt  the  existence  of 
the  disease  as  a  result  of  syphilis. 

The  writer  has  seen  excess  of  deeply  staining  megalocytes,  and  megalo- 
blasts, in  several  cases  of  moderate  severity  shortly  after  florid  syphilis,  both 
in  adults  and  infants,  and  has  come  to  regard  the  differential  diagnosis  of 
severe  secondary  anemia  in  syphilitic  subjects  from  progressive  pernicious 
anemia,  as  one  of  the  most  difficult  fields  in  blood-analysis.  From  experi- 
ence at  the  autopsy-table  it  has  been  very  apparent,  however,  that  most 
cases  showing  advanced  or  active  tertiary  lesions  have  shown  types  of 
secondary  anemia.  The  subject  requires  much  more  extensive  clinical  and 
pathological  observation. 

Malaria. — Although  there  are  in  the  literature  numerous  cases  of  so- 
called  pernicious  anemia  referred  to  malarial  infection,  the  fact  that 
the  typical  changes  of  the  disease  may  be  established  as  a  result  of 
chronic  malaria  was  not  demonstrated  until  Bignami  and  Dionisi  re- 
ported their  study  of  the  marrow  of  fatal  cases.  Here  were  found  the 
signs  of  megaloblastic  hyperplasia  in  distinct  form.  Among  the 
writer's  Montauk  cases  there  were  no  less  than  19  in  which  the  blood 
showed  a  majority  of  megalocytes  with  increased  Hb,  and  a  considerable 
number  of  megaloblasts,  and  in  one  of  these  the  lymphoid  marrow  was 
found  markedly  hyperplastic,  with  excess  of  megaloblasts,  and  an  enor- 
mous number  of  young  estivo-autumnal  parasites.  In  all  these  cases 
the  condition  had  become  established  within  8-10  weeks  from  the  be- 
ginning of  the  infections,  but  the  malarial  element  had  doubtless  been 
aided  by  exposure  and  poor  food. 

The  frequency  of  these  cases  among  malarial  subjects  and  the  fact 
that  the  bone  marrow  suffers  in  a  peculiar  way  in  many  cases  of  estivo- 
autumnal  infection,  are  considerations  which  bear  directly  on  the 
myelogenous  origin  of  pernicious  anemia. 

Typhoid  Pever. — Quincke  and  Rosenstein  each  report  the  transfor- 
mation of  the  cachexia  of  typhoid  fever  into  pernicious  anemia  but  in 
neither  case  do  their  reports  show  the  presence  of  typical  changes  in 
the  blood,  both  falling  in  the  class  of  severe  secondary  anemia. 

Gastro-intestinal  Disorders. — The  largest  group  of  cases  and  those 
which  from  the  first  have  given  most  support  to  the  theory  of  the 
cryptogenic  origin  of  the  disease  have  been  referred  to  disturbance  of 
the  gastro-intestinal  tract.  A  certain  number  of  these  cases  have 
shown  at  autopsy  well-marked  lesions  of  stomach  or  intestines  which 
have  been  deemed  a  sufficient  cause  of  the  anemia,  while  in  others  the 
stomach  and  intestines  have  been  found  normal  and  the  theory  of  in- 


180  PROGRESSIVE  PERNICIOUS  ANEMIA. 

testinal  auto-intoxication  has  been  elaborated,  principally  by  Hunter, 
to  account  for  the  anemia. 

1 .  Lesions  of  Gastro-intestinal  Tract. — Chronic  gastritis  or 
enteritis  with  fatty  degeneration  of  the  secreting  cells  of  the  peptic 
and  intestinal  glands,  followed  by  atrophy  and  sclerosis  of  the  mucosa 
have  been  demonstrated  by  Ponfick,  Nothnagel,  Fenwick,  Levy, 
Brabazon,  Nolen,  Eisenlohr,^  Osier,  Ewald,  Marti  us,  Koch,  and  Stengel. 

Ewald  found  this  condition  of  the  gastric  or  intestinal  mucosa  in  all 
his  subjects  examined  at  autopsy  and  believes  that  such  changes,  which 
he  calls  aiiadenia,  are  responsible  for  all  "  idiopathic  "  cases,  but  Im- 
merman  and  Quincke  had  previously  shown  that  anadenia  is  not  found 
in  all  cases  of  clearly  protopathic  origin,  and  this  claim  has  been 
verified  by  recent  observers.  The  writer  has  secured  excellently  pre- 
served peptic  and  intestinal  glands  and  intact  lymphoid  structures 
from  an  acute  case  showing  no  visceral  lesions  to  which  the  anemia 
could  be  referred,  and  Eisenlohr  and  Martins  have  reported  extensive 
atrophy  of  intestinal  mucosa  in  cases  showing  no  gastro-intestinal  dis- 
turbance and  slight  anemia. 

Stenosis  of  the  pylorus  as  a  result  of  annular  carcinoma  or  of  chronic 
gastritis,  with  extreme  atrophy  and  contraction  of  the  stomach,  has 
been  demonstrated  in  a  considerable  number  of  cases.  (Israel, 
Ehrlich,  Renvers.) 

In  two  of  the  writer's  autopsies  the  stomach  was  markedly  contracted, 
the  pylorus  was  tightly  steuosed,  admitting  a  lead  pencil  with  difficulty  ; 
the  mucosa  showed  the  changes  of  well  marked  chronic  gastritis,  but  the 
constriction  of  the  pylorus  was  the  result  of  chronic  productive  inflammation 
and  not  of  carcinoma.  These  cases  lasted  two  and  four  years,  with  inter- 
vals of  improyement,  but  finally  died  with  typical  blood  changes  and  with- 
out marked  emaciation. 

Other  cases  with  annular  or  circumscribed  carcinoma  of  jyi/Iorus  have 
been  reported  as  showing  typical  changes  in  the  blood.  The  writer 
has  not  yet  seen  any  case  of  cancer  of  the  stomach  in  which  the 
lesions  in  the  blood  were  indistinguishable  from  the  classical  type  of 
progressive  pernicious  anemia.  Lazarus  reports  genuine  cases  follow- 
ing small  pyloric  cancers  only. 

A  "neurotic  atrophy'^  of  intestinal  mucosa  has  been  suggested  as  an 
etiological  factor  by  Banti,  Jurgens  (1882),  Blaschko  (1883),  and  Sasaki 
(1884),  who  found  parenchymatous  degeneration  of  ganglion  cells  in  Meiss- 
ner's  and  Auerbach's  plexuses,  but  Scheimpflug  has  shown  that  no  such  im- 
portant deductions  were  warranted  from  the  changes  demonstrable  at  that 
time  in  sympathetic  ganglia,  since  identical  changes  occur  in  many  other 
conditions.  Peculiar  eosinophile  globules  have  been  described  by  Lubarsch, 
Koch,  and  Sasaki,  in  the  atrophic  adenoid  tissue  of  chronic  gastritis,  and 
these  bodies  have  been  regarded  as  pathognomonic  of  this  condition  and  of 
significance  in  the  anemia,  but  Hammarschlag  has  seen  them  in  gastric 
cancer,  and  the  writer,  in  the  normal  stomach  at  autopsy  1  hour  after  death 
from  ether. 

The  mesenteric  lymph  nodes  have  been  found  hyperplastic,  in  one  in- 
stance caseous,  by  Eichhorst,  Quincke,  and  others.  This  condition  was 
present  in  some  of  the  writer's  autopsies,  but  not  in  all,  while  in  a  case  of 


SPECIAL  ETIOLOGY.  181 

profound  secondary  anemia,  probably  of  syphilitic  origin,  nearly  all  the 
abdominal  lymph  nodes  were  enlarged  and  caseous,  but  there  were  no 
megaloblastic  changes  in  the  blood. 

It  is  therefore  obvious  that  all  the  gastro-intestinal  lesions  thus  far  de- 
scribed in  cases  of  jirogressive  j^ernicious  anemia  have  been  seen  in  other 
conditions  and  that  none  of  them  can  be  regarded  as  specific  lesions  in  the 
disease.  That  many  of  the  above  lesions,  however,  especially  the 
marked  atrophic  conditions,  may  act  as  occasional  exciting  causes  of 
progressive  pernicious  anemia,  as  of  secondary  anemia,  seems  equally 
probable.  Yet,  not  a  few  observers  regard  them  all  as  secondary  to  the 
anemia,  or  as  unimportant  associated  lesions,  while  Faber  and  Bloch 
believe  that  the  atrophy  of  the  intestinal  mucosa  described  in  many 
cases  is  always  a  cadaveric  alteration. 

2.  Functional  Disturbances  of  Gastro-intestinal  Tract. — 
The  prominence  of  the  gastro-intestinal  symptoms  of  the  disease  has 
from  the  first  directed  special  attention  to  the  study  of  functional  dis- 
turbances in  the  alimentary  tract. 

The  reports  of  Sandoz  were  apparently  the  first  to  seriously 
strengthen  the  impression  that  some  of  the  most  typical  cases  of  per- 
nicious anemia  are  of  intestinal  autotoxic  origin,  this  observer  finding 
that  apparently  genuine  cases  were  sometimes  cured  by  vigorous  gas- 
tric lavage,  enteroclysis,  and  the  administration  of  intestinal  antiseptics 
and  laxatives.  This  observation  has  since  been  fully  verified  and  the 
opinion  has  steadily  grown  that  the  most  frequent  if  not  the  essential 
cause  of  progressive  pernicious  anemia  is  found  in  a  peculiar  toxemia 
of  intestinal  origin,  with  or  without  organic  lesions  of  the  mucosa. 
The  evidence  supporting  this  opinion  has  accumulated  from  many  sides. 

The  results  of  intestinal  antiseptic  treatment  has  steadily  pointed  in 
this  direction.  The  observations  on  bothriocephalus  anemia  have  re- 
cently given  significant  evidence  to  a  similar  effect  (q.  v.).  Signs  of 
increased  intestinal  putrefaction  have  been  noted  in  the  excessive  indi- 
canuria  of  the  disease  (Senator,  Muller,  Brieger,  Hennige,  Grawitz, 
Schaumann),  and  in  the  presence  of  cadaverin  and  putrescin  in  the  urine 
of  certain  cases  (Hunter).  In  a  very  acute  case  examined  at  autopsy 
by  the  writer  the  odor  of  H.^S  from  the  intestines  was  very  intense, 
but  in  other  cases  there  was  very  slight  evidence  of  this  putrefactive 
product. 

Hunter's  studies  in  this  field  are  undoubtedly  the  most  important 
experimental  contribution  to  the  etiology  of  the  disease  that  has  yet 
been  made.  His  conclusions  are,  briefly,  that  pernicious  anemia  is  a 
specific  clinical  condition,  resulting  from  excessive  hematolysis  occur- 
ring chiefly  in  the  portal  system  and  brought  about  by  intestinal  in- 
toxication in  which  the  products  of  growth  of  specific  bacteria  are 
probably  concerned. 

Reviewing  the  knowledge  of  the  pathological  changes  in  the  blood  and 
marrow,  spleen,  and  lymph  nodes,  Hunter  concludes  that  there  is  no  known 
characteristic  lesion  of  the  disease,  although  the  high  Hb-index  of  the  blood 
he  regards  as  very  important  and  an  almost  pathognomonic  sign.     Turning 


182  PROGRESSIVE  PERNICIOUS  ANEMIA. 

to  the  liver  he  finds  in  the  studies  of  Peters  proof  that  in  the  anemia  of  wast- 
ing diseases  there  is  no  markedly  excessive  deposit  of  iron  in  the  liver,  and 
finds  that  in  no  disease  bearing  any  clinical  resemblance  to  pernicious 
anemia  does  the  deposit  of  iron  in  the  liver  approach  in  any  degree  that 
characteristic  of  pernicious  anemia.  Moreover,  this  deposit  is  largely 
limited  to  the  outer  two-thirds  of  the  lobules,  a  position  in  which  the  scanty 
deposits  of  other  conditions  (extravasation  of  blood,  chronic  congestion)  are 
never  limited.  From  the  comparison  of  chemical  analyses  he  finds  that 
the  liver  in  pernicious  anemia  contains  on  the  average  seven  times  as  much 
iron  as  in  any  other  diseases  attended  with  anemia,  while  the  iron  content 
of  the  spleen  is  not  notably  increased.  He  therefore  concludes  that  per- 
nicious anemia  consists  essentially  in  excessive  hematolysis,  occurring  prin- 
cipally in  the  liver.  Why  Hunter  limits  the  blood  destruction  to  the  portal 
system  is  not  entirely  clear,  but  he  reasons  as  follows :  Malaria,  par- 
oxysmal hemoglobinemia,  and  poisoning  by  pyrogallic  acid  cause  general 
hemoglobinemia  and  hemoglobinuria,  with  deposits  in  the  liver  unlike  those 
of  pernicious  anemia,  while  in  this  disease  and  in  poisoning  by  toluylendia- 
min  there  is  never  any  Hb  in  the  urine,  but  in  each  case  the  iron  in  the  liver 
is  found  in  the  same  position.  Since  toluylendiamin  exerts  a  specific  stimu 
lating  action  on  the  liver  cells  he  believes  the  poison  of  pernicious  anemia 
must  be  directed  especially  against  the  liver  and  hence  be  found  principally 
in  the  portal  sj'stem,  a  source  which  is  further  indicated  by  the  frequency  of 
gastro-intestiual  symptoms. 

Hunter's  studies  are  chiefly  important  in  the  demonstration  of  the  pecu- 
liar behavior  of  the  liver  in  ridding  the  blood  of  iron,  but  the  theory  of 
portal  hematolysis  by  intestinal  intoxication,  while  doubtless  strongly  sug- 
gested by  his  results,  is  still  far  from  demonstration.  He  has  recently 
attributed  to  bacteria  from  decaying  teeth,  and  to  chronic  infectious  gastro- 
enteritis from  this  source,  an  essential  part  in  the  etiology  of  the  disease. 

Although  extensive  deposits  of  iron  in  the  liver  and  the  limitation  of  the 
pigment  to  the  outer  portions  of  the  lobules  have  since  been  shown  to  occur 
in  other  diseases  (Russell,  Hindenlang),  and  cases  of  pernicious  anemia 
have  been  reported  in  which  no  excess  of  iron  was  found  in  the  liver  (Ran- 
som), Hunter  has  demonstrated  characteristic  if  not  pathognomonic  features 
in  the  pathological  anatomy  of  the  disease. 

Myelogenous  Origin. — There  are  recorded  a  moderate  number  of  ob- 
servations which  suggest  that  progressive  pernicious  anemia  may  re- 
sult directly  from  lesions  affecting  the  normal  physiology  of  the  bone 
marrow.  Chief  among  these  is  the  case  of  general  sarcomatosis  of 
bone  marrow  described  by  P.  Grawitz^  as  accompanied  by  typical 
changes  in  the  blood.  Litten  (1877),  reported  a  case  of  pernicious 
anemia  followed  by  leukemia  in  which  there  were  multiple  abscesses 
in  the  bone  marrow,  but  the  diagnosis  of  pernicious  anemia  appears 
doubtful.  Waldstein  in  1882  saw  a  similar  case  in  which  the  marrow 
was  the  seat  of  a  peculiar  change  said  to  have  resembled  in  structural 
details  a  chloroma  found  in  the  mediastinum.  This  case  also  is  ob- 
scure. 

Grawitz  believes  that  the  severe  anemia  sometimes  following  in- 
fectious processes  is  to  be  referred  to  changes  in  the  marrow  instituted 
during  the  course  of  the  infection.  The  frequent  occurrence  of  per- 
nicious anemia  after  malaria  appears  to  have  similar  import. 

Nervous  Origin. — The  prominent  participation  of  the  nervous  system 
in  the  anatomical  lesions  of  the  disease  has  often  raised  a  suspicion  in 
many  minds  that  some  of  these  lesions  might  be  primary.     Except  in 


HISTOLOGICAL   CHANGES  IN  THE  MARROW.  183 

the  case  of  the  abdominal  sympathetic  none  of  the  lesions  have  been 
long  claimed  to  hold  such  a  position  in  the  pathology  of  the  disease, 
and  at  present  it  is  generally  accepted  that  the  central  nervous  sys- 
tem suffers  only  secondarily  from  the  anemia  or  as  the  result  of  as- 
sociated conditions. 

Likewise  the  functional  disturbances  of  the  nervous  system  cannot 
be  claimed  to  act  as  more  than  somewhat  distant  predisposing  causes, 
although  McKenzie  and  Curtin  have  referred  to  certain  cases  as  having 
originated  directly  from  nervous  shock. 

Infectious  Origin. — Pernicious  anemia  has  not  escaped  classification 
among  infectious  diseases ;  by  Klebs,  who  claimed  to  have  observed 
flagellate  bodies  in  the  fresh  blood  ;  by  Frankenhauser  and  Petrone, 
who  reported  the  isolation  of  leptothrices  in  several  cases  ;  by  Bernheim, 
who  isolated  a  bacillus  from  the  blood  of  one  case  after  death  ;  and  by 
Perles,  who  observed  highly  refractive,  very  actively  ameboid  bodies 
in  several  cases. 

Histological  Changes  in  the  Marrow. — Cohnheim's  original  report 
on  the  changes  in  the  marrow  of  a  case  of  pernicious  anemia  described 
the  presence  throughout  the  shafts  of  the  long  bones  of  lymphoid  mar- 
row which  contained  no  fat  cells  but  was  composed  of  a  small  number 
of  colorless  myelocytes  and  of  many  red  cells  most  of  which  were 
nucleated  and  of  unusually  large  size.  This  observation  was  verified 
by  many  later  investigators,  especially  by  Rindfleisch,  Ehrlich,  Miiir, 
Muller,^  but  its  importance  was  greatly  obscured  by  the  reports  by 
Neumann,  Litten,  Grohe,  and  others,  that  chronic  diseases  causing 
cachexia  also  lead  to  an  hyperplasia  of  red  marrow  in  the  shafts  of 
long  bones.  Neumann,  and  Litten  and  Orth,  claimed  also  to  have  in- 
duced identical  changes  in  the  marrow  by  subjecting  animals  to  repeated 
hemorrhages.  In  1886  Geelmuyden  claimed  that  the  hyperplastic 
marrow  in  such  chronic  diseases  does  not  differ  in  structure  from  that 
of  normal  lymphoid  marrow  except  in  regard  to  the  Hb-content  of 
the  red  cells,  and  that  the  hyperplasia  here  represents  merely  a  simple 
physiological  increase  in  functional  capacity.  He  showed  also  that 
while  the  hyperplastic  marrow  in  pernicious  anemia  is  very  extensive, 
occupying  as  much  as  82  percent  of  the  cavities  of  long  bones,  and  is 
firm  and  cellular,  much  of  the  marrow  of  secondary  anemia  is  apt  to 
be  gelatinous  with  comparatively  few  cells,  while  the  hyperplasia 
seldom  becomes  half  as  extensive  as  in  pernicious  anemia. 

The  writer,  from  a  study  of  the  marrow  in  cases  of  grave  secondary 
anemia,  showing  in  the  blood  many  megalocytes,  observed  that  the 
limits  of  the  hyperplasia  are  seldom  very  extensive,  that  the  nucleated 
red  cells  are  usually  relatively  scarce  and  of  smaller  size  instead  of 
being  over  abundant  and  of  very  large  size  as  in  pernicious  anemia. 
These  observations  merely  corroborate  in  minor  details  the  original 
claim  of  Cohnheim  and  Rindfleisch. 

Yet  the  essential  importance  of  the  changes  in  the  mari'ow  is  again 
brought  into  question  by  the  reports  of  cases  of  pernicious  anemia  in 
which  the  usual  alterations  in  this  tissue  are  wanting. 


184:  PROGRESSIVE  PERNICIOUS  ANEMIA. 

Six  such  cases,  reported  by  Laache  and  Quincke,  and  one  by  Geelmuyden, 
date  from  too  early  a  period  to  figure  in  the  present  discussion,  but  Ehrlich  2 
in  1888  reported  a  case  of  fatal  acute  anemia  in  a  "bleeder"  who  suffered 
principally  from  metrorrhagia  and  in  whose  blood  the  red  cells  were  reduced 
to  215,000,  the  majority  of  them  being  undersized,  while  nucleated  red  cells 
were  absent,  and  there  was  apparently  no  hyperplasia  of  the  lymphoid  mar- 
row. Engel  has  recently  reported  a  very  similar  case.  In  1893  the  writer^ 
observed  an  apparently  similar  condition  in  a  boy  of  18  years,  of  Cuban 
parentage,  who  had  always  appeared  pale,  and  whose  sister  was  extremely 
pale  and  moderately  anemic.  The  patient  suffered  from  uncontrollable 
epistaxis,  finally  from  intestinal  hemorrhages,  for  three  weeks  before  death. 
During  the  last  week  the  red  cells  numbered  456,000,  the  leucocytes  were 
reduced  in  number,  there  were  no  megaloblasts  and  no  megalocytes,  the 
majority  of  red  cells  being  oval  and  undersized.  No  autopsy  was  secured, 
but  the  anemia  appeared  clearly  to  be  of  idiopathic  origin. 

Ehrlich,  Lazarus,  and  Engel  drew  the  conclusion  from  such  cases  that 
pernicious  anemia  is  not  necessarily  associated  with  hyperplasia  of  the 
lymphoid  marrow. 

The  writer  has  encountered  other  cases  which  seem  to  fall  in  this  class, 
and  for  which  the  term  "microcytic  type  of  pernicious  anemia"  has  been 
suggested,  but  he  has  always  felt  that  the  grounds  for  their  classification 
with  other  acute  cases  showing  megaloblasts  and  megalocytes  are  at  present 
entirely  inadequate.  The  reports  of  Ehrlich  do  not  offer  any  evidence  to 
prove  the  relation  of  these  two  types  of  anemia,  and  it  seems  entirely  pre- 
mature to  draw  from  such  cases  any  conclusions  regarding  the  pathological 
anatomy  and  pathogenesis  of  true  pernicious  anemia. 

The  extent  of  the  hyperplasia  of  lymphoid  marrow  may  vary  from 
the  involvement  of  the  entire  shafts  of  all  long  bones  to  the  appear- 
ance in  smaller  foci  only  of  the  megaloblastic  changes.  The  latter 
condition  is  probably  seen  daring  the  transformation  of  a  grave  sec- 
ondary to  a  pernicious  anemia.  Hyperplastic  lymphoid  marrow  may 
be  found  in  one  long  bone  while  in  others  the  marrow  is  normal. 
(Lazarus.) 

Histologically,  the  marrow  in  milder  cases  shows  a  considerable 
number  of  normal  red  cells,  always  less  than  in  the  circulation,  a  few 
normoblasts,  and  a  greater  number  of  megaloblasts  sometimes  lying  in 
"  islands,"  w^hile  in  a  remarkable  case  of  Rindfleisch's  nearly  all  of  the 
cells  in  the  marrow  were  large  megaloblasts.  In  most  of  the  writer's 
cases  the  neutrophile  myelocytes  were  distinctly  deficient,  the  princi- 
pal colorless  cells  being  large,  hyaline,  and  mononuclear.  The  eosins 
are  usually  deficient.  Evidences  of  active  destruction  of  blood  cells 
are  seen  in  the  presence  of  macrophages  inclosing  many  red  cells, 
and  of  many  pigmented  cells.  The  megaloblasts  may  reach  an  ex- 
treme size,  50  /u  (Rindfleisch),  their  nuclei  are  usually  eccentric,  and 
in  various  stages  of  degeneration,  while  the  cell  body  is  polychromatic 
and  very  densely  staining,  or  fragmented  and  pale. 

Not  only  the  grade,  but  the  type  of  lesion  in  the  marrow  appears  to 
vary  in  different  cases.  The  writer  has  encountered  three  rather  dis- 
tinct conditions  in  the  marrow  of  ribs,  vertebra,  and  femur,  of  fatal 
cases  of  idiopathic  pernicious  anemia. 

1.  The  Cohxheim-Rindfleisch  type  (megaloblastic  degex- 
eration),  in  which  with  wide  extension  of  lymphoid  marrow  an  exces- 


HISTOLOGICAL    CHANGES  IN  THE  MARROW.  185 

sive  proportion  of  the  cells  in  the  marrow,  and  nearly  all  the  nucleated 
red  cells,  are  megaloblasts  or  gigantoblasts. 

2.  Extreme  lymphoid  hyperplasia  (myeloblastic  degexer- 
ation),  in  which  the  majority  of  cells  are  small,  hyaline,  and  mononu- 
clear, while  nucleated  red  cells  are  scarce,  and  those  remaining  are  of 
large  size.  This  type  of  lesion  is  identical  with  that  recently  described 
by  Nagaeli,  under  the  term  "  myeloblastic  degeneration." 

According  to  Nagaeli,  in  pernicious  anemia  the  hyperplastic  marrow  con- 
tains 95  percent  of  cells,  a  little  larger  than  lymphocytes,  non  granular, 
moderately  basophile,  with  reticulated  nuclei.  These  cells  he  calls  myelo- 
blasts and  claims  that  they  are  the  ancestral  forms  of  myelocytes.  He  finds 
them  in  small  numbers  in  the  blood  of  pernicious  anemia,  and  secondary 
anemia,  and  very  abundantly  in  leukemia.  (The  writer  has  been  unable  to 
convince  himself  that  these  cells  are  not  large  and  medium  sized  lympho- 
cytes.) 

3.  Recently  the  writer  encountered  a  case  of  fatal  pernicious  anemia 
of  twelve  months'  duration,  without  demonstrable  origin,  in  which  the 
marrow  showed  a  remarkable  excess  of  nucleated  red  cells  of  normal 
size. 

Nature  of  the  Megaloblastic  Changes  in  the  Marrow. — If  Cohnheim's 
belief  is  accepted  that  changes  in  the  marrow  in  pernicious  anemia 
constitute  a  reversion  of  that  tissue  to  the  embryonal  type  in  the  for- 
mation of  red  cells,  pernicious  anemia  must  be  regarded  as  identical 
with  or  very  closely  related  to  a  neoplasm  involving  the  red  cells. 
This  view  is  accepted  by  Rindfleisch  and  Ehrlich,  but  the  latter,  how- 
ever, does  not  apparently  press  the  somewhat  strained  relation  to  a 
tumor  formation. 

The  review  of  otir  knowledge  of  the  development  of  the  blood,  con- 
tained in  Chapter  IV.,  shows  that  the  cellular  processes  concerned  in 
the  formation  of  red  cells  are  virtually  the  same  both  in  adult  and  in 
fetal  life.  In  both  periods  the  non-nucleated  discs  are  the  result  of 
mitotic  division  of  several  series  of  erythroblasts,  each  new  series  con- 
taining more  and  more  Hb,  until  by  a  process  not  yet  fully  understood 
the  non-nucleated  disc  springs  from  the  last  series,  i.  e.,  the  normo- 
blast. In  both  adult  and  embryonal  lymphoid  marrow  the  earlier 
series  of  nucleated  Hb-holding  cells  appear  to  be  nearly  equally  repre- 
sented, while  at  no  period  of  embryonal  life  are  very  large  mitotic 
polychromatophilic  cells  seen  such  as  abound  in  the  marrow  of  acute 
pernicious  anemia,  and  under  no  other  conditions  does  the  marrow  con- 
tain such  an  excess  of  the  large  megaloblasts  as  in  this  disease.  The 
essential  difference  between  the  normal  formation  of  red  cells  in  the 
adult  and  their  defective  development  in  pernicious  anemia  consists  in 
the  failure  of  the  later  more  highly  specialized  series  of  erythroblasts, 
I.  e.,  the  normoblast.  This  of  course  is  the  fundamental  nature  of  a 
tumor  formation,  in  which  the  highly  specialized  properly  functionat- 
ing tissues  are  replaced  by  excessively  cellular,  poorly  differentiated 
structures,  subject  to  a  great  variety  of  degenerative  changes. 

Although  the  gigantoblast  of  pernicious  anemia  is  never  seen  in  em- 


186  PROGRESSIVE  PERNICIOUS  ANEMIA. 

bryonal  blood-forming  organs,  such  aberrant  forms  seem  to  result  from 
secondary  degenerative  processes,  while  it  is  the  absence  of  normoblasts 
which  is  the  more  important  anomaly  of  blood  formation  in  the  disease. 
The  investigations  of  the  thirty  years  that  have  intervened  since  Cohn- 
heim  concluded  (1868)  that  pernicious  anemia  is  a  reversion  to  the  em- 
bryonal type  of  blood  formation  seem  to  have  in  a  considerable  degree 
verified  his  belief.  To  what  extent  pernicious  anemia  follows  the  laws 
known  to  govern  the  occurrence  and  behavior  of  tumors  is  an  impor- 
tant inquiry  which  cannot  here  be  further  considered. 

Pathogenesis  of  the  Disease. — Progressive  pernicious  anemia  is  believed 
by  some  to  result  through  defective  hematogenesis,  and  by  others  primarily 
from  excessive  hematolysis,  to  which  is  added  secondarily  defective  hemato- 
genesis. 

The  latter  view  is  based  principally  upon  the  abundant  evidence  of  exces- 
sive hematolysis  which  is  undoubtedly  the  prominent  external  feature  of  the 
disease,  upon  the  reported  occurrence  of  cases  of  pernicious  anemia  which 
were  rapidly  fatal  without  yielding  evidence  of  defective  hematogenesis  in 
the  megaloblastic  changes  in  the  marrow,  and  upon  experimental  evidence 
that  the  prolonged  action  of  certain  blood  solvents,  toluylendiamin,  etc.,  may 
lead  to  a  condition  very  similar  to  progressive  pernicious  anemia.  To  some 
extent  this  opinion  is  favored  also  by  the  results  of  repeated  losses  of  blood 
which  have  been  shown  to  lead  to  a  condition  closely  resembling  progressive 
pernicious  anemia  both  in  the  blood  and  in  the  marrow.  (Neumann.)  More- 
over in  many  cases  of  grave  secoudary  anemia  the  blood  often  approaches  in 
character  that  of  the  cryptogenic  anemia,  and  this  fact  has  been  accepted  as 
favoring  the  hematolytic  theory,  although  in  cancer  of  the  stomach,  which 
leads  to  some  of  tlie  severest  grades  of  secondary  anemia,  defective  blood 
formation  seems  quite  as  likely  to  figure  in  the  anemia  as  does  excessive 
hematolysis.  The  acceptance  of  this  view  involves  the  admission  that  the 
changes  in  the  marrow  are  secondary  to  the  destruction  of  blood  and  are 
therefore  not  pathognomonic  of  the  disease. 

The  writer  has  always  felt  that  the  correct  conception  of  the  disease  ac- 
cording to  present  knowledge  is  as  a  process  of  defective  hematogenesis  in 
which  megaloblastic  degeneration  of  the  marrow  is  the  pathognomonic  tissue 
lesion  and  excessive  hematolysis  a  constant  result. 

Hematolysis  undoubtedly  precedes  in  many  instances  defective  hemato- 
genesis, but  it  is  a  different  kind  of  hematolysis  from  that  which  occurs  after 
the  megaloblastic  changes  have  become  established.  The  peculiar  de- 
struction of  blood  cells  seen  in  pernicious  anemia,  marked  by  excessive  de- 
posits of  iron,  by  hemoglobinuria,  pathological  urobilinuria,  by  phagocytic 
englobement  of  red  cells  in  the  marrow,  and  by  peculiar  clinical  symptoms, 
appears  to  be  possible  only  when  red  cells  are  defectively  formed. 

Most  convincing  demonstration  of  the  propriety  of  this  view  was  encoun- 
tered on  comparing  a  case  of  profound  secondary  anemia  from  chronic  ulcer 
of  the  duodenum  with  a  rapidly  fatal  case  of  the  cryptogenic  disease.  In 
the  former  case,  although  the  Hb  registered  only  10  percent  and  the  red 
cells  were  below  one  million,  there  were  only  slight  changes  in  the  size  of 
the  cells  and  the  patient  improved  under  iron.  In  the  latter  case,  the  Hb  reg- 
istered 38  percent  on  first  examination,  the  red  cells  1,780,000,  but  megalo- 
cytes  and  megaloblasts  were  abundant  and  the  patient  died  after  an  acute 
illness  of  four  weeks.  The  essential  difference  between  these  cases  appears 
clearly  to  have  been  not  in  the  destruction  or  loss  of  blood  but  in  its  forma- 
tion. 

It  has  been  amply  shown  that  the  system  can  replace  enormous  losses  if 
conditions  are  favorable  for  the  normal  production  of  blood.  Lazarus  quotes 
the  example  of  a  Russian  physician  whose  health  remained  little  affected  by 


CHANGES  IN  THE  BLOOD.  187 

the  loss  of  about  four  times  the  entire  volume  of  blood  by  consecutive  pul- 
monary hemorrhages  in  the  course  of  a  few  months.  This  author  also  refers 
to  cases  of  cancer  of  the  stomach  in  which  the  anemia  remained  compara- 
tively harmless  until  suddenly  changing  from  the  secondary  type  witli  low 
Hb  index  to  the  primary  with  increased  Hb-iudex  and  appearance  of  megalo- 
blasts.     {Die  Anaemie,  p.  43.) 

The  attempted  experimental  production  of  pernicious  anemia  by  the  use 
of  blood  solvents,  etc.,  may  or  may  not  have  been  partly  successful,  as  indi- 
cated bj'  Neumann's  studies,  but  their  outcome  can  hardly  alter  the  fact  that 
blood  destruction  may  be  continued  over  long  periods  without  giving  the 
typical  picture  of  pernicious  anemia  which  is  at  once  evident  in  clinical  ob- 
servation when  defective  hematogenesis  is  added  to  the  long-existent  hema- 
tolysis. 

In  view  of  these  and  many  similar  considerations  it  would  seem  that  the 
belief  is  justified  that  it  is  the  megaloblastic  degeneration  of  the  lymphoid 
marrow  which  constitutes  pernicious  anemia  a  separate  clinical  and  path- 
ological entity.  Hematolysis  may,  and  in  some  instances  does,  precede,  in 
point  of  time,  the  changes  in  the  marrow,  as  in  the  pernicious  anemia  fol- 
lowing malarial  cachexia,  but  this  destructive  influence  at  once  takes  on  a 
new  character  and  produces  specific  results  when  acting  on  defectively  formed 
cells,  as  is  shown  by  the  comparison  of  the  iron  content  of  the  liver  in  sec- 
ondary and  in  progressive  pernicious  anemia. 

The  occurrence  of  rapidly  fatal  cases  of  the  disease  and  the  transformation 
of  a  grave  secondary  anemia  (cancer  of  pylorus)  into  true  pernicious  anemia 
may  be  explained  by  a  rapid  and  general  or  slow  and  partial  establishment 
of  the  marrow  changes.  In  the  former  case  the  changes  in  the  blood  will  be 
pronounced  from  the  first,  in  the  latter  it  may  be  difficult  to  determine  the 
exact  point  when  a  grave  secondary  becomes  a  true  pernicious  anemia. 

Changes  in  the  Blood. 

Chemistry. — The  specific  gravity  of  the  blood  is  constantly  reduced, 
owing  to  the  loss  of  both  the  albumens  of  the  plasma  and  the  Hb  of  the 
red  cells.  The  gravity  is  here  a  much  less  reliable  indication  of  the 
Hb-content  than  in  chlorosis,  in  which  the  Hb  alone  is  markedly  af- 
fected. (Hammarschlag,  Dieballa.)  Nevertheless,  it  is  just  in  this  dis- 
ease that  the  information  furnished  by  the  specific  gravity  is  of  peculiar 
interest,  as  it  concerns  those  principles  in  the  plasma  of  which  little 
can  be  learned  by  other,  simple,  clinical  tests. 

Grawitz  finds  that  the  specific  gravity  of  the  blood  may  fall  below 
1.030,  or  below  that  of  normal  serum.  Dieballa  had  two  cases  show- 
ing a  gravity  of  1.028,  with  red  cells  404,000  and  500,000,  while 
Copeman,  using  Roy's  method,  reported  a  case  with  a  gravity  of  1.027. 
That  there  is  no  close  relationship  between  the  numbers  of  red  cells 
and  the  specific  gravity  appears  in  Dieballa's  tables  in  which  a  gravity 
of  1.038  was  obtained  in  one  case  showing  784,000  cells  and  in  an- 
other with  1.4  million  cells.  The  total  albumens  of  the  blood  are  much 
reduced,  but  the  loss  affects  principally  the  red  cells.  Grawitz  finds 
the  loss  of  albumens  of  the  serum  to  be  distinctly  greater  in  secondary 
anemia  than  in  progressive  pernicious  anemia. 

The  great  reduction  in  total  albumen  of  the  blood  is  indicated  by 
the  low  percentage  of  dry  residue  found  by  v.  Jaksch,  Grawitz,  and 
Stintzing  and  Gumprecht,  who  in  very  severe  cases  obtained    between 


188  PROGRESSIVE  PERNICIOUS  ANEMIA. 

9  percent  and  12  percent  (normal  20-24  percent),  while  the  red  cells 
numbered  between  534,000  and  1.7  million.  That  the  loss  of  albumen 
is  due  principally  to  the  changes  in  the  red  cells  appears  from  the  fact 
that  the  specific  gravity  and  dry  residue  of  the  serum  are  but  slightly 
altered  even  in  severe  cases. 

Thus  Grawitz  found  a  gravity  of  the  serum  of  1.024  (normal  1.027- 
1.029),  dry  residue  7.08  percent  (normal  10-10.5),  while  the  gravity 
of  the  blood  fell  to  1.036,  and  its  dry  residue  to  11.45  percent  (nor- 
mal 21-24  percent).  While  the  albumens  of  the  blood  were  reduced 
therefore  one  half,  those  of  the  serum  fell  only  one  fifth.  Similar  results 
were  obtained  by  Dieballa.  This  loss  of  albumens  of  the  whole  blood 
must  be  referred  to  the  loss  of  fibrinogen  and  to  the  diminution  of  red 
cells.  V.  Jaksch's  analyses '  of  red  cells  in  pernicious  anemia  led  him 
to  conclude  that  those  remaining  are  abnormally  rich  in  albumens,  a 
view  which  may  seem  to  accord  with  the  large  size  of  these  cells.  By 
estimating  the  N  of  100  gr.  of  centrifuged  red  cells  he  obtained  6.48 
grm.  N,  40.5  grm.  alb.  (normal  34.5).  Grawitz's  analyses  however 
do  not  support  this  conclusion. 

The  relatively  high  proportion  of  albumen  in  the  serum  in  perni- 
cious anemia  distinguishes  this  disease,  as  Grawitz  has  shown,  from 
many  forms  of  secondary  anemia  arising  from  hemorrhage,  malignant 
tumors,  etc.,  with  which  the  albumens  of  the  serum  are  much  reduced. 

The  resistance  of  the  red  cells  has  not  apparently  been  tested, 
although  Limbeck  (p.  163)  found  their  isotonic  tension  somewhat  in- 
creased (resistance  diminished)  in  two  cases  of  grave  anemia. 

Copeman  noted  that  the  hemoglobin  crystallized  readily  from  the 
blood  of  a  case  of  pernicious  anemia,  while  it  is  very  difficult  to  obtain 
such  crystals  from  normal  human  blood. 

Morphological  Changes. — The  whole  blood  is  much  reduced 
in  quantity  as  is  shown  by  the  scanty  content  of  vessels  and  viscera  at 
autopsy,  and  by  the  imperfect  filling  of  the  superficial  vessels  during 
life.  This  reduction  in  bulk  is  often  so  marked  as  not  to  require  for 
its  demonstration  any  attempts  at  accurate  measurement. 

Coagulation  is  very  feeble  so  that  on  standing  it  was  early  noted 
(Ponfick)  that  the  red  cells  settle  to  the  bottom,  the  leucocytes  form  a 
middle  layer  of  variable  depth,  while  the  plasma  deposits  nearly  all  its 
cells  without  interference  from  clotting.  To  the  feeble  clotting  is 
probably  referable  the  very  slow  separation  of  serum  from  the  clot,  as 
observed  by  Lenoble. 

The  color  of  the  blood  may  in  mild  cases  be  almost  normal ;  it  is 
usually  very  pale ;  while  in  extreme  cases  visible  currents  of  colorless 
serum  mingle  with  the  drop  on  very  slight  pressure.  On  this  account 
a  liberal  puncture  may  be  required  to  obtain  a  drop  suitable  for  exam- 
ination. A  v^ery  dark  color  has  been  observed  by  Furbringer  and,  after 
transfusion,  by  Gusserow. 

Hemoglobin. — The  percentage  of  Hb  varies  from  a  moderate  reduc- 
tion (70  percent)  to  such  a  low  point  that  accurate  estimates  are  im- 
possible, while  the  Fleischl  instrument  indicates  less  than  10  percent. 


PLATE    V. 


Progressive  Pernicious  Anemia.    (Eosin  and  Methylene  Blue.) 


Fig. 

I. 

Figs 

.  2. 

Fig. 

3- 

Fig. 

4- 

Figs 

•5- 

Fig. 

6. 

Fig. 

7- 

Fig. 

8. 

Fig. 

9- 

Fig. 

lO. 

Megalocyte  with  excess  of  Hb. 

Microycte  with  excess  of  Hb. 

Microcyte  deficient  in  Hb. 

Poikilocyte  deficient  in  Hb. 

Poikilocyte  witli  excess  of  Hb. 

Polychromasia  of  Maragliano. 

Megaloblast,  resting  vesicular  nucleus,  basophilic  granules  in  cytoplasm. 

Microblast. 

Megaloblast  in  mitosis.     Thread  stage. 

Megaloblast.      Pathological  mitosis. 


CHANGES  IN  THE  BLOOD.  189 

In  the  average  case  the  Hb  registers  between  20-40  percent.  A 
rather  high  percentage  of  Hb  with  severe  clinical  symptoms  and  pro- 
nounced morphological  changes  in  the  red  cells  is  not  infrequently 
seen.  Lazarus  refers  to  a  case  showing  65-70  percent  but  otherwise 
with  pronounced  symptoms.  The  Hb  is  usually  not  so  low  as  in 
secondary  anemias  of  equal  severity. 

A  RELATIVELY  HIGH  Hb-index  is  One  of  the  characteristic  features 
of  the  blood.  In  many  cases,  especially  when  the  megalocytes  are 
very  abundant,  the  Hb-index  is  above  normal  (1-1.75)  and  in  such 
cases  the  index  is  apt  to  rise  as  the  anemia  increases,  and  to  fall  dur- 
ing intervals  of  improvement.  In  a  larger  group  of  cases  the  index 
does  not  vary  greatly  from  the  normal,  when  the  excess  of  Hb  in 
megalocytes  balances  the  loss  in  other  cells.  In  other  cases  the  index 
is  for  long  periods  below  normal,  but  still  relatively  high  as  compared 
with  secondary  anemia  and  chlorosis.  Thus  the  Hb-index  in  chlorosis 
averages  about  .50  (Cabot,  Bramwell),  but  in  pernicious  anemia  the 
index  seldom  approaches  that  figure.  The  low  Hb-index  is  usually 
seen  in  chronic  cases,  while  the  highest  indices  obtained  by  the  writer 
were  in  more  rapid  cases  especially  just  before  death. 

In  some  cases  of  secondary  anemia  the  Hb-index  may  approach  the 
normal,  so  that  comparatively  little  diagnostic  importance  can  attach 
to  the  lesser  grades  of  increase  in  Hb. 

Red  Cells. — In  the  average  case  of  established  pernicious  anemia  the 
red  cells  vary  slightly  above  or  below  one  mill  ion.  Well-marked  mor- 
phological changes  may  exist,  however,  when  the  red  cells  number 
over  two  millions,  but  earlier  stages  of  the  disease  have  so  far  escaped 
notice,  indicating  that  preexisting  anemia  is  an  essential  predisposing 
condition. 

Although  Quincke  reported  143,000  red  cells  in  a  case  which  recov- 
ered and  Hayem  292,500  in  a  fatal  case,  more  recent  reliable  statistics 
show  that  life  is  seldom  prolonged  when  the  cells  fall  below  400,000. 
Even  this  extremely  low  proportion  is  below  the  count  in  many  fatal 
cases,  as  many  patients  succumb  when  the  red  cells  are  about  one 
million.  Most  fatal  cases  show  at  death  between  300,000  and  600,- 
000  red  cells.  The  reduction  in  cells,  in  cases  under  treatment,  seldom 
progresses  uniformly,  intervals  of  improvement,  followed  by  rapid  re- 
lapses, continuing  till  the  end. 

Changes  in  the  form,  size,  and  staining  reaction  of  the  cells  are  even 
more  important  than  their  reduction  in  number. 

While  the  largest  cells  of  normal  blood  measure  about  9  ft  across,  in 
pernicious  anemia  the  increased  size  of  the  cells  is  characteristic  of 
the  disease,  the  averas^e  diameter  being-  estimated  bv  Lazarus  at  11-13 
fj.,  while  some  may  reach  a  diameter  of  16—18  /Jt.  (Askanazy.)  Cases 
vary  greatly  in  regard  to  the  extent  and  uniformity  of  this  lesion.  In 
one  of  the  writer's  cases,  not  of  unusual  gravity,  at  least  90  percent 
of  the  cells  measured  from  11-16  /jl.  Megaloblasts  were  very  numer- 
ous, and  microcytes  extremely  rare.  It  may  be  said  that  wdess  Jo  per- 
cent of  the  cells  are  distinctly  oversized  the  diagnosis  of  pernicious  anemia 


190  PROGRESSIVE  PERNICIOUS  ANEMIA. 

should  be  made  with  reserve.  Usually,  but  not  always,  the  proportion 
of  megalocytes  accords  with  the  severity  of  the  condition.  Lazarus 
found  in  8  severe  cases  56—71  percent  of  megalocytes,  in  5  cases  dur- 
ing periods  of  improvement  33-50  percent,  or  during  complete  remis- 
sions 0-14  percent. 

The  Hb-content  of  these  megalocytes  is  in  typical  cases  distinctly 
increased  and  the  cell  is  flat  and  uniformly  opaque  instead  of  showing 
the  bi-concave  discoid  shape.  The  writer  has  found  this  character  of 
the  megalocytes  a  very  reliable  differential  sign  between  true  perni- 
cious anemia  and  the  grave  secondary  anemia  of  cancer,  etc.  In  the 
latter  conditions  the  great  majority  of  megalocytes  are  usually  deficient 
in  Hb.     (Cf.  Plates  V.  and  VI.) 

MiCROCYTES  are  a  somewhat  less  characteristic  cell-form  in  perni- 
cious anemia.  They  may  be  only  slightly  under  normal  size  or  be 
found  in  severe  cases  as  mere  points  of  reddish  staining  protoplasm 
not  over  1  tx  in  diameter.  They  may  contain  an  excess  or  deficiency 
of  Hb.  In  the  early  stages  of  the  disease  the  writer  has  found  them 
less  frequent,  but  in  moribund  cases  they  rarely  fail  to  appear  in  con- 
siderable numbers.  The  division  of  forms  between  megalocytes  and 
microcytes  is  then  often  complete,  no  normal  cells  remaining. 

Deformed  red  cells  (poikilocytes)  of  all  sizes  are  commonly 
present  in  considerable  numbers,  probably  resulting  from  the  ameboid 
properties  of  the  cells  and  frequently  from  traumatism.  The  oval  shape 
of  many  cells  both  large  and  small  was  early  noted  by  Osier  and  Gard- 
ner, and  in  some  cases  this  character  is  very  prominent,  for  reasons 
which  are  not  clear.  Pear-shaped  cells  are  perhaps  the  most  common 
form,  the  narrow  point  representing  a  pseudopodium.  Cells  very  defi- 
cient in  Hb  are  apt  to  bend  into  horseshoe  or  pessary  shapes.  Cells 
rich  in  Hb  less  often  become  deformed. 

Ameboid  motion  of  red  cells  in  pernicious  anemia  may  be  observed 
in  fresh  preparations.  The  moving  cells  usually  content  themselves 
with  the  extrusion  of  pseudopodia,  and  with  changes  in  shape  which 
Muir  and  Gulland  believe  are  not  true  ameboid  phenomena,  but  the 
writer  has  seen  active  locomotion  of  lenticular  microcytes. 

Nucleated  red  cells  may  be  said  to  occur  in  all  cases  of  perni- 
cious anemia,  but  their  demonstration  sometimes  requires  prolonged 
search.  It  has  been  shown  by  Ehrlich  and  verified  by  nearly  all  later 
observers,  that  megaIohlast%  constitute  the  majority  of  such  cells  in  per- 
nicious anemia  and  there  is  at  present  no  ground  on  which  to  deny 
their  pathognomonic  significance,  when  present  in  large  numbers.  In 
typical  cases  of  the  disease  they  are  almost  or  quite  exclusively  present, 
while  normoblasts  are  commonly  absent.  Their  numbers  seem  to  de- 
pend largely  on  disturbances  of  the  circulation  and  other  accidents,  but 
Ehrlich  claims  that  the  extent  of  the  megaloblastic  degeneration  of  the 
marrow  may  be  determined  by  the  numbers  of  these  cells  in  the  blood. 
This  rule  probably  holds  in  general,  but  in  the  writer's  experience 
there  have  been  exceptions.  In  other  cases  both  normoblasts  and 
megaloblasts  appear  in  the  blood,  in  which  case  it  is  found  that  the 


PLATE    VI 


Secondary  Pernicious  Anaeniia.     (Eosin  and  Methylene  Blue. 


Figs.  I.  Megalocytes. 

Fig.  2.  Red  cells  of  normal  size,  deficient  in  Hb. 

Fig.  3.  Microcyte  deficient  in  Hb. 

Fig.  4.  Red  cell  showing  granular  degeneration.     (Punctate  basophilia.) 

Fig.  5.  Megalocyte  with  excess  of  Hb.     (Polychromasia  of  Gabritschewsky.) 

Fig.  6.  Polynuclear  leucocyte.     Xodal  points  of  cytoreticiihini. 


k 


CHANGES  IN  THE  BLOOD.  191 

megaloblasts  outnumber  the  normoblasts,  indicating  that  the  defective 
formation  of  cells  has  become  uppermost. 

From  the  considerations  mentioned  under  the  etiology  and  patho- 
genesis of  the  disease  it  will  be  seen  that  the  crucial  point  in  the  diag- 
nosis between  secondary  and  pernicious  anemia  is  encountered  in  prac- 
tice, in  the  proportions  of  normoblasts  and  megaloblasts  to  be  found  in 
the  blood.  If,  as  appears  to  be  fully  attested,  a  grave  secondary  may 
be  transformed  into  pernicious  anemia,  the  change  must  consist  pri- 
marily in  a  megaloblastic  degeneration  in  some  portion  of  the  marrow. 
The  normoblasts  of  the  circulation  must  then  be  gradually  replaced 
by  megaloblasts. 

These  theoretical  deductions  appear  to  be  borne  out  in  clinical  experience 
since  the  appearance  of  megaloblasts  accompanies  a  more  severe  type  of 
anemia.  Lazarus  finds  normoblasts  rarely  associated  with  megaloblasts,  and 
this  has  been  the  writer's  experience,  except  in  children,  in  whom  both  are 
frequently  found  together.  Schaumann  saw  both  forms  in  all  his  cases  of 
bothriocephalus.  Cabot  noted  that  megaloblasts  and  normoblasts  are  fre- 
quently associated  in  pernicious  anemia  and  that  the  former  increase  when 
the  disease  grows  worse.  Askanazy  found  many  megaloblasts  in  a  case  of 
bothriocephalus,  while  after  expulsion  of  the  worms  they  were  steadily  re- 
placed by  normoblasts.  Dorn  observed  an  idiopathic  case  promptly  improve 
after  the  sudden  appearance  of  many  normoblasts.  From  Coles'  extensive 
observations  in  two  cases  it  is  seen  that  there  may  be  very  marked  varia- 
tions in  the  numbers  and  to  a  less  extent  in  the  proportions  of  normoblasts 
and  megaloblasts  in  the  blood,  and  that  in  the  early  stages  of  the  disease 
normoblasts  may  predominate.  On  both  clinical  and  pathological  grounds 
therefore  it  is  justified  to  class  an  anemia  as  pernicious  when  the  megaloblasts  out- 
number the  normoblasts,  or  when  any  considerable  proportion  {33  percent)  of  the 
red  cells  are  megalocytes  with  increased  Hb. 

A  question  frequently  arises  regarding  the  value  of  a  prolonged 
search  for  megaloblasts  in  order  to  establish  the  diagnosis  of  pernicious 
anemia,  since  if  only  one  nucleated  cell  be  found  and  that  a  megalo- 
blast  the  chances  favor  the  presence  of  an  excess  of  such  cells  over 
normoblasts.  It  is  quite  possible,  however,  that  the  first  few  nucleated 
cells  should  be  of  large  size  while  the  next  three  or  four  prove  to  be 
normoblasts,  and  it  appears  much  more  rational  to  base  the  diagnosis 
upon  the  general  morphology  of  the  blood  and  on  all  the  clinical  data, 
than  to  rely  upon  any  single  isolated  sign.  Nevertheless  the  discovery 
of  a  single  very  large  megaloblast  with  abnormal  nucleus  is  virtually  a 
pathognomonic  sign  of  pernicious  anemia. 

The  numbers  of  nucleated  red  cells  in  pernicious  anemia  vary  greatly. 
Frequently  they  are  scarce  and  their  demonstration  requires  patient 
searching.  Or,  of  two  slides  taken  at  the  same  time  one  may  contain 
several  and  the  other  apparently  none.  Usually  they  increase  with 
the  severity  of  the  blood  changes.  The  occurrence  of  normoblastic 
blood-crises  has  been  referred  to  (Dorn)  as  a  favorable  sign.  Coles 
found  over  6,000  nucleated  red  cells  per  cmm.,  the  majority  of  large 
size,  in  a  fatal  case.  The  writer  has  found  them  unusually  abundant 
in  a  case  in  which  nearly  all  the  red  cells  were  very  large,  and  has  seen 


192  PROGRESSIVE  PERNICIOUS  ANEMIA. 

them  nearly  as  numerous  as  the  leucocytes  during  ante-mortem  leuco- 
cytosis.     Distinct  microblasts  are  comparatively  rare. 

The  occurrence  of  mitotic  nuclei  in  megaloblasts,  first  described  by 
Luzet,  is  usually  limited  to  the  severer  stages  of  the  disease,  in  which 
their  presence  is  pathognomonic  of  the  condition.  Schaumann,  how- 
ever, found  them  in  a  case  that  recovered.  The  presence  of  three  or 
more  unequal  asters  in  one  gigantoblast,  as  occasionally  found  in  se- 
vere cases  is  one  of  the  most  significant  pathological  signs  within  the 
range  of  blood  analysis.     (Plate  V.,  Fig.  10.) 

Degenerative  changes  in  the  red  cells  not  only  cause  the 
appearance  of  abnormal  cell  forms  but  lead  to  a  series  of  chemical  and 
morphological  alterations  plainly  demonstrable  in  stained  specimens. 
Poli/chromatophilia,  referring  to  the  development  of  a  brownish  stain- 
ing quality  of  the  Hb  is  constantly  present,  usually  more  marked  in 
the  severer  cases.  It  appears  probable  that  the  change  is  in  some  cells 
preliminary  to  the  solution  of  Hb  in  the  plasma,  but  according  to 
Engel  it  indicates  very  rapid  formation  of  cells  and  incomplete  meta- 
morphosis of  nucleus.  It  is  most  marked  and  nearly  constantly  present 
in  megaloblasts,  some  of  which  stain  diffusely  brownish  blue. 

Uemoglobinemia  is  constantly  present  in  the  severer  cases  and  is  in- 
dicated by  a  distinct  brownish  red  staining  quality  of  the  dried  plasma. 

Punctate  BASOPHILIA  (granular  degeneration  (Grawitz^))  of  red 
cells  is  of  moderately  frequent  occurrence  both  in  megalocytes  and  es- 
pecially in  megaloblasts.  As  previously  shown,  this  abnormality  is 
sometimes  referable  in  the  megaloblasts  of  pernicious  anemia  to  karyo- 
rhexis  of  degenerating  nuclei.  In  other  cells  the  blue  granules  are 
probably  reappearing  particles  of  the  nuclear  remnant  of  ordinary  red 
cells.     (Maximow.) 

ScHiSTOCYTOSis,  or  the  separation  of  fragments  of  red  cells,  is,  ac- 
cording to  Ehrlich,  the  mode  of  origin  of  many  microcytes  in  per- 
nicious anemia. 

Hydremia  of  red  cells  probably  causes  many  smaller  cells  to  appear 
much  larger  than  normal.  It  has  already  been  shown  that  hydremia 
of  the  plasma  is  probably  responsible  for  the  increased  diameter  of 
many  red  cells,  but  in  pernicious  anemia  the  majority  of  megalocytes, 
especially  those  with  increased  Hb,  are  undoubtedly  derived  from 
megaloblasts. 

Absence  of  rouleaux  is  a  constant  and  very  characteristic  feature 
of  the  disease,  and  results  not  only  from  the  reduction  in  the  number 
of  cells  but  principally  from  chemical  changes  in  their  membranes  and 
protoplasm. 

The  Leucocytes. — In  well  established  cases  the  leucocytes  are 
markedly  reduced  in  number.  This  condition  is  clearly  referable  to  the 
megaloblastic  lesion  in  the  marrow,  which  leads  to  an  excessive  pro- 
liferation of  megaloblasts  at  the  expense  of  other  marrow  cells.  (Rind- 
fleisch.)  Progressive  hypoleucocytosis  is  the  rule,  the  white  cells  fall- 
ing very  low  in  extreme  cases.  (1,500-2,000,  Hayem.)  Of  the 
colorless  cells  which  remain,  a  diminished  proportion  are  neutrophile. 


RESUME  OF  THE  CHIEF  FACTS.  193 

the  majority  being  large  and  small  basophilic  cells.  With  the  reduc- 
tion in  total  numbers  there  is  a  relative  lymphocytosis,  very  slight  in 
the  mild  cases,  and  very  marked  (79  percent,  Cabot)  in  severe  stages. 
The  eoslnophUe  cells  usually  vary  within  low  normal  limits.  In  the 
severer  cases  they  are  apt  to  be  reduced  (Grawitz,  p.  102),  and  rarely 
may  be  absent  (Cabot),  but,  contrary  to  Neusser's  belief,  they  are  very 
scarce  in  mild  and  present  in  some  fatal  cases.  In  the  marrow,  the 
writer  has  found  them  usually  much  reduced  in  number.  Myelocytes 
are  usually  present  in  small  numbers,  Cabot  finding  them  in  42  of  52 
cases.  The  writer  finds  these  cells  in  pernicious  anemia  almost  invari- 
ably of  the  smaller  type,  but  has  seen  isolated  specimens  of  the  larger 
(Cornil's)  neutrophile  cell,  which  is  abundant  in  leukemia. 

Mast-cells  were  increased  in  some  of  the  Avriter's  marrow  smears,  but 
he  has  never  seen  more  than  single  examples  in  the  blood  smear. 

Hyperleucocytosis  in  pernicious  anemia  occurs  as  the  result  of  com- 
plications, as  an  ante-mortem  phenomenon,  rarely  without  discoverable 
cause  in  course  of  the  disease,  and  in  one  case  (Dorn)  it  appeared  to 
be  associated  with  a  normoblastic  blood  crisis,  and  heralded  a  favor- 
able turn  in  the  disease. 


RESUME   OF  THE   CHIEF  FACTS  CONCERNING  PROGRESSIVE 
PERNICIOUS  ANEMIA. 

Definition. — The  terra  should  be  applied  to  all  forms  of  grave 
anemia  showing  an  excess  of  megaloblasts  over  normoblasts,  or  at 
least  33  percent  of  megalocytes  (or  less  during  remissions). 

Etiology, — The  largest  group  of  cases  remains  of  cryptogenic  origin 
but  is  possibly  to  be  referred  to  intestinal  intoxication.  Various  lesions 
of  the  gastro-intestinal  tract  are  underlying  causes,  including  chronic 
gastritis  with  or  without  stenosis  of  pylorus,  and  small  carcinomata  of 
pylorus. 

Of  intestinal  parasites,  Bothriocephalus  latus  certainly,  and  other 
parasites  possibly,  lead  to  the  disease. 

Repeated  hemorrhages  in  rare  instances  cause  typical  pernicious 
anemia.  Pregnancy  has  no  specific  influence,  but  the  cases  which  fol- 
low parturition  are  probably  referable  to  hemorrhage  and  various  un- 
hy genie  conditions. 

The  disease  is  referable  to  pernicious  malaria  often  ;  to  syphilis,  j^ro- 
longed  diarrhea,  bad  hygienic  conditions,  probably ;  to  typhoid  fever, 
yellow  fever,  and  other  infectious  diseases,  doubtfully ;  but  not  to  func- 
tional or  organic  disturbances  of  the  nervous  system. 

Lymphosarcoma  of  the  marrow  was  present  in  one  reported  case. 

Pathological  Anatomy. — The  essential  lesion  of  the  disease  is  a 
megaloblastic  metaplasia  of  the  lymphoid  marrow  which  is  invariably 
present,  is  pathognomonic  of  the  disease,  and  in  many  respects  re- 
sembles a  tumor  formation  aifecting  the  progenitors  of  the  red  cells. 

Pathogenesis. — The  disease  does  not  exist  until  defectively  formed 
red  cells  are  being  destroyed  in  large  numbers  by  some  hemolytic  agent. 
13 


194  PROGRESSIVE  PERNICIOUS  ANE3IIA. 

Changes  in  the  Blood. — The  red  cells  may  be  reduced  to  about 
200,000,  but  usually  number  about  one  million.  Megalocytes  with 
increased  Hb  constitute  from  33  percent  to  90  percent  of  the  cells, 
but  during  remissions  they  may  be  very  scanty. 

Megaloblasts  are  very  scarce,  or  very  numerous,  and  are  either  ex- 
clusively present,  or  outnumber  the  normoblasts.     Microblasts  are  rare. 

The  Hb-index  varies,  but  in  the  advancing  stages  it  is  usually  above 
normal,  or  during  periods  of  improvement  or  remission  may  be  below 
normal.  If  below  normal,  it  is  usually  higher  than  in  any  other  form 
of  anemia. 

In  the  fresh  blood  coagulation  is  very  feeble,  rouleaux  do  not  form, 
there  are  doubtful  evidences  of  ameboid  motion  of  poikilocytes,  but 
occasionally  active  locomotion  of  microcytes.  Hemoglobinemia  often 
exists,  but  is  sometimes,  possibly,  an  artifact. 

Degenerative  changes  in  red  cells  are  extensive,  including  poikilo- 
cytosis,  schistocytosis,  diminished  resistance  and  solution  of  red  cells, 
polychromasia  (Gabritschewsky),  punctate  basophilia  and  karyorhexis 
in  megalocytes  and  megaloblasts. 

Leucocytes  are  usually  reduced,  in  proportion  to  the  severity  of  the 
lesion  in  the  marrow  and  the  progress  of  the  disease,  and  relative  lym- 
phocytosis is  the  rule.  Leucocytosis  arises  usually  from  complications, 
rarely  with  "blood  crises,"  and  often  just  before  death.  Eosins  are 
commonly  deficient  and  a  few  medium-sized  myelocytes  can  usually  be 
found. 

Chemistry. — The  blood  is  much  reduced  in  bulk.  The  specific 
gravity  has  no  constant  relation  to  the  number  of  red  cells  or  propor- 
tion of  Hb,  but  follows  the  loss  of  albumens,  of  cells,  and  of  plasma. 
It  may  fall  as  low  as  1.027.  The  albumens  and  specific  gravity  of 
the  serum  are  much  less  reduced  than  in  grave  secondary  anemias. 
The  resistance  of  the  red  cells  is  reduced  and  Hb  may  crystallize  read- 
ily. The  hydremia  of  the  plasma  affects  the  red  cells  and  is  probably 
lesponsible  for  some  of  their  increase  in  size. 

The  Diagnosis  may  rest  upon  the  presence  of: — numerous  megalo- 
blasts and  megalocytes  with  increased  Hb  ;  33  percent  of  megalocytes        ; 
with  increased  Hb ;  an   excess  of  megaloblasts  over  normoblasts ;  a 
single  gigantoblast  or  megaloblast  in  pathological  mitosis. 

The  diagnosis  cannot  rest  on  an  extreme  reduction  of  red  cells.  | 

The  diagnosis  may  require  the  complete  summation  of  all  clinical        1 
and  morphological  data,  as  well  as  observation  on  the  course  of  the 
disease,  or  even  the  microscopical  examination  of  the  marrow.  s 

The  cases  of  fatal  idiopathic  anemia  of  microcytic  type  (Ehrlich,        | 
Engel,  et  al.)  cannot  at  present  be  classed  with  the  Addison-Biermer 
progressive  pernicious  anemia. 

The  prognosis  is  very  difficult  to  determine. 

The    most    severe    case    on    record    recovered.      (Quincke's    with        | 
143,000  (?)  red  cells.)     Severe  cases  of  cryptogenic  origin  may  recover. 
The  most  unfavorable  are  the  very  acute  idiopathic  cases,  and  those  of 
slower  development  from  gastro-intestinal  lesions. 


BIBLIOGRAPHY.  195 

The  sudden  development  of  well-marked  changes  in  the  blood  com- 
monly indicates  a  severe  course  but  such  cases  have  recovered.  The 
slow  relapsing  cases,  with  gradual  changes  in  the  blood  and  absence 
of  raegaloblasts  usually  die  from  their  anemia. 

A  high  Hb-index  goes  with  well-marked  changes  in  the  blood  and 
marrow  and  is  of  unfavorable  import.  Lower  Hb-indices  are  seen  in 
chronic  cases  and  in  remissions  of  more  acute  cases. 

A  reduction  to  600,000-700,000  red  cells  in  this  disease  is  seldom 
survived.  Marked  degenerative  changes  in  megalocytes  and  megalo- 
blasts,  and  marked  hemoglobinemia  go  with  the  severe  cases. 

Extreme  reduction  of  neutrophile  and  eosinophile  leucocytes  is  an 
unfavorable  sign ;  while  leucocytosis  commonly  precedes  death  by  a 
few  days. 

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BIBLIOGRAPHY.  197 


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CHAPTER    VIII. 
LEUKEMIA. 

Historical. — Probable  cases  of  leukemia  were  observed  and  com- 
mented  upon  from  the  beginning  of  the  19th  century  by  Bichat,  1801, 
Andral,  1823,  Hodgkin,  1832,  Donne,  1830,  and  many  others,  and  the 
disease  was  imperfectly  recognized  in  current  text-books  (Piorry, 
Velpeau,  Rokitansky)  in  which  it  was  regarded  as  an  obscure  suppura- 
tive "hematitis"  (Piorry).  Donne,  however,  in  1839,  found  in  his 
case  at  autopsy  that  the  blood  cells  were  more  than  one  half  "  white  or 
mucous  globules,"  and  attributed  the  disease  to  a  failure  of  transforma- 
tion of  the  leucocytes  into  red  cells. 

The  first  step  in  the  elucidation  of  the  disease  was  made  when  Craigie, 
in  1841,  demonstrated  an  entire  absence  of  suppurative  foci  in  the  body 
and  concluded  that  the  purulent  material  was  absorbed  from  the  en- 
larged spleen  of  which  the  histological  structure  "  does  not  favor  the 
gathering  of  pus  in  abscesses." 

In  the  same  issue  of  the  Edinburgh  Medical  Journal,  Bennett  de- 
scribed a  second  case,  demonstrating  an  entire  absence  of  suppurative 
foci,  describing  accurately  the  gross  appearance  of  the  blood  in  bulk, 
and  under  the  microscope  recognizing  the  leucocytes  as  identical  in  ap- 
pearance with  pus  cells,  and  adding  to  the  lesion  in  the  spleen  a  uni- 
form enlargement  of  lymph  nodes.  Regarding  the  nature  of  the 
disease  he  concluded  that  the  excess  of  leucocytes  in  the  blood  must  be 
classed  as  pus ;  that  in  this  case  the  pus  was  formed,  entirely  from  the 
action  of  a  zymotic  principle  in  the  blood,  quite  apart  from  inflamma- 
tory processes  ;  and  that  the  enlargement  of  the  liver  and  spleen  and 
the  pyoid  condition  of  the  blood  "  lead  us  to  conjecture  that  in  some 
way  they  stand  in  the  relation  of  cause  and  effect." 

Virchow,  a  few  weeks  later,  described  a  case  complicated  by  super- 
ficial abscesses,  and  termed  the  condition  "  weisses  blut "  or  leukemia. 
In  a  series  of  later  articles  he  distinguished  more  clearly  than  Bennett 
had  done  between  pyemia  and  leukemia,  and  emphasized  the  relation 
between  the  changes  in  the  blood  and  the  lesions  in  the  blood-forming 
organs,  holding  the  disease  to  be  a  primary  affection  of  these  organs. 

In  1851  Bennett  contributed  the  first  monograph  on  the  disease, 
collecting  37  cases,  describing  and  depicting  the  microscopical  appear- 
ance of  the  blood,  reporting  the  first  chemical  analyses,  giving  very 
reliable  descriptions  of  the  symptomatology  and  pathological  anatomy, 
reporting  cases  of  idiopathic  splenic  tumor  without  leukemia,  and 
employing  the  term  leucocythemia  as  preferable  to  leukemia. 

In  1847  Virchow  observed  a  case  in  which  the  spleen  was   very 


HISTORICAL.  199 

slightly  and  the  lymph  nodes  greatly  enlarged,  and  in  his  review  of 
the  subject  in  1853  he  pointed  out  the  grounds  for  division  of  the  dis- 
ease into  splenic  and  lymphatic  varieties.  The  chief  of  these  grounds 
was  the  presence  in  the  blood  of  the  above  case  of  cells  which  resembled, 
those  of  the  lymph  nodes. 

The  leucocytosis  was  first  demonstrated  during  life  by  Fuller  (1846), 
who  also  believed  that  the  alterations  in  the  blood  were  not  of  in- 
flammatory origin.  In  1851  Vogel,  also,  demonstrated  the  leucocytosis 
during  life  and  attempted  to  count  the  cells. 

In  1869  Neumann  ^  described  the  lesions  of  the  marrow,  demonstrat- 
ing the  origin  of  the  myelogenous  variety  of  the  disease,  and  his  obser-, 
vations  were  verified  and  extended  by  Waldeyer  (1871).  Ponfick  noted 
that  in  some  cases  the  marrow  is  light  yellow  and  puriform,  while  in 
others  it  retains  more  or  less  fleshy  color,  a  variation  which  he  referred 
to  the  extent  of  the  cellular  hyperplasia.  The  hyperplasia  of  the 
gastro-intestinal  lymphatic  structures  and  metastatic  tumors  of  the 
pleura  were  described  by  Friedrich  in  1857,  while  the  enlargement  of 
the  liver  was  referred  to  collections  of  cells  probably  derived  from  the 
blood,  by  Bottger  in  1858. 

In  the  morphology  of  the  blood  it  was  shown  by  Bennett  and  Vir- 
chow,  that  the  leucocytes  of  the  blood  were  identical  in  appearance 
with  those  of  pus,  although  Virchow  was  careful  to  point  out  that  they 
were  not  therefore  of  similar  significance.  These  early  observers  both 
described  the  cells  as  mononuclear,  or  polynuclear,  or  devoid  of  nucleus 
(Virchow),  and  granular  or  hyaline.  Virchow  and  most  others  mistook 
the  eosinophile  granules  for  fat  particles.  In  his  case  of  lymphatic 
leukemia  Virchow  described  the  cells  of  the  blood  as  resembling  those 
of  the  lymph  nodes. 

No  important  advance  in  the  knowledge  of  the  minute  structure  of 
leukemic  blood  cells  was  made  until  Schultz  and  Erb  in  1865  classi- 
fied leucocytes  according  to  the  character  of  their  protoplasm.  Neu- 
mann's discovery  of  the  myelogenous  type  of  the  disease  also  directed 
more  careful  attention  to  the  characters  of  the  new  leucocytes  and 
strengthened  the  suspicion  that  the  new  cells  of  leukemic  blood  were 
not  all  of  the  same  varieties  as  seen  in  normal  blood.  The  question 
was  finally  settled  by  Hosier"  who  punctured  the  sternum  during  life 
and  secured  from  the  marrow  large  numbers  of  the  identical  cells  seen 
in  the  peripheral  circulation.  It  was  at  once  concluded  that  these 
cells  must  be  characteristic  of  the  myelogenous  type  of  the  disease. 

In  1879-80,  Ehrlich's  studies  aclded  greatly  to  the  knowledge  of 
leukemic  changes  in  the  blood  and  were  especially  important  in  per- 
mitting greater  accuracy  in  diagnosis.  It  then  for  the  first  time  be- 
came possible  to  distinguish  all  cases  of  lymphatic  from  myelogenous 
leukemia,  and  to  recognize  early  stages  and  other  obscure  phases  of  the 
latter  type  of  the  disease.  The  first  pure  case  of  myelogenous  leuke- 
mia was  described  by  Litten.* 

In  the  diagnosis  of  leukemia  Ehrlich  was  able  to  find  in  the  blood 
three  chief  signs:    (1)  Mononuclear  cells  with  neutrophile  granules. 


200  LEUKEMIA. 

(2)  an  increased  number  of  eosinophile  cells,  and  (3)  normoblasts  or, 
later,  megaloblasts. 

His  conclusion  that  an  increase  of  eosinophile  cells,  first  noted  by 
Jaderholm  and  Schwarze,  is  pathognomonic  of  the  disease  was  soon 
relinquished.  As  shown  by  MuUer  and  Rieder,  it  is  not  so  much  the 
increased  numbers  but  the  peculiar  forms  of  eosinophile  cells  which 
are  characteristic  of  leukemia,  although  their  numerical  excess  is  often 
of  itself  pathognomonic.  The  ueutropliile  myelocytes,  as  long  before 
claimed  by  Hosier,  were  therefore  again  accepted  as  the  most  important 
cell  form.  Through  the  contributions  of  Hosier,^  Ehrlich,  Cornil, 
Muller,^  Limbeck,  Rieder,  Troje,  and  many  others,  it  was  shown  that 
these  cells  are  derivatives  of  the  marrow  and  probably  peculiar  to  the 
blood  of  leukemia.  The  diagnostic  importance  of  Cornil's  large  mye- 
locytes with  pale  eccentric  nucleus  was  established  through  the  obser- 
vations of  Eberth,  Eisenlohr,  Hosier,  Litten,  Hayem,  and  especially 
of  H.  F.  Huller. 

Later,  it  came  to  be  recognized  that  neutrophile  myelocytes  are  oc- 
casionally seen  in  small  numbers  in  many  other  conditions.  Conse- 
quently there  remained  as  a  diagnostic  feature  of  the  blood  only  the 
presence  of  a  large  proportion  of  myelocytes,  and  it  was  seen  that  the 
genuineness  of  some  previously  reported  cases  was  open  to  doubt  {e.  g., 
Litten's). 

Absence  of  ameboid  motion  in  the  myelocytes  of  leukemia  was  de- 
monstrated by  Biesiadecki,  L5wit,^  Hayem,  Huller,  Gilbert,  Rieder, 
and  others.  That  this  loss  of  ameboid  motion  is  associated  with  a  loss 
of  reproductive  capacity  was  stated  by  Hayet.^  A  ])artial  loss  of  ame- 
boid activity  of  other  leucocytes  was  observed  by  Neumann  and 
Cavafy,  while  J.  Weiss  does  not  admit  any  difference  in  ameboid 
properties  of  the  white  cells  of  leukemia  and  of  other  leucocytes. 

The  discovery  of  nucleated  red  cells  was  followed  by  their  demon- 
stration in  the  blood  of  leukemic  cadavers  by  Erb,  Bottger^  and 
Klebs,^  and  in  the  circulating  blood  by  Neumann.^  The  comparative 
absence  of  these  cells  in  lymphemia  was  first  noted  by  Hayem,  and 
verified  by  Wertheim,  Rieder,  and  Dock.  Hegaloblasts  were  first 
distinguished  in  leukemia  by  Ehrlich's  pupil  Utheman,  and  by  Troje. 

Likewise  the  discovery  of  mitotic  division  of  leucocytes  by  Flem- 
ming  and  Arnold  led  after  a  time  to  the  demonstration  of  mitotic 
figures  in  the  white  cells  of  both  the  viscera  and  the  blood  of  leukemia. 
(Arnold,  1884;  Hayem,  1889;  H.  F.  Huller,  1889.) 

Acute  leukemia  was  first  described  by  Friedrich  in  1857,  in  a  case 
lasting  6  weeks.  Other  reports  of  similar  cases  were  added  slowly,  so 
that  in  1889  Ebstein  collected  16  cases  lasting  from  5-20  weeks, 
many  of  which  appear  to  have  been  of  the  lymphatic  variety. 

The  knowledge  of  the  chemistry  o^  the  blood  has  kept  pace  with  that 
of  the  morphology.  The  first  chemical  analyses  were  those  of  Robert- 
son, 1850  (January),  and  of  Parkes,  while  a  few  mouths  later  Strecker 
examined  the  blood  of  a  case  of  Yogel's.  Later  important  contribu- 
tions  were   made   by  Becquerel,  Robin  and  Schercr.     In  these  early 


ETIOLOGY.  201 

analyses  the  chief  chemical  alterations  in  the  blood  were  fully  indicated. 
The  specific  gravity  of  the  blood  was  found  as  low  as  1.036-1 .049,  that 
of  the  serum  1 .023-1.029.  The  iron  was  shown  to  be  markedly  dimin- 
ished and  the  proportion  of  water  increased,  with  a  loss  of  albumens, 
especially  of  the  red  cells.  Scherer  reported  the  isolation  of  several 
organic  acids  in  considerable  traces,  and  of  hypoxanthin,  a  body  pre- 
viously isolated  from  the  spleen,  while  the  presence  of  increased  uric 
acid  was  demonstrated  by  both  Scherer  and  Parkes,  and  later  by 
Fowlwarckzny,  Koerner,  and  Mosler.  The  later  chemical  analyses  of 
leukemic  blood  and  tissues  have  been  contributed  by  Stintzing  and 
Gumprecht,  Limbeck,^  v.  Jaksch,  Salkowski,  Bockendahl  and  Land- 
wehr,  Freund  and  Obermayer.^ 

Etiology.  Age. — The  histories  of  the  earliest  cases  (Bennett)  indi- 
cated that  the  disease  may  occur  at  almost  any  period  of  life.  Later 
statistics  showed  that  in  the  male  sex  the  liability  increases  from 
childhood  to  the  thirtieth  or  fortieth  years,  thereafter  declining.  In 
women  most  cases  occur  during  active  sexual  life.  In  infants,  cases 
have  been  noted  from  birth,  but  the  few  cases  recorded  in  childhood 
indicate  that  this  period  is  comparatively  immune.  Audeod  observed 
the  disease  in  56  children;  in  the  1st  year  11  times;  2-4  years,  12; 
5-9  years,  12;  10-15  years,  21  ;  the  majority  were  boys.  Of  135 
cases  collected  by  Ehrlich,  Grawitz,  Litten,  87  were  males,  48  females. 

Heredity  has  figured  in  some  remarkable  cases  but  its  influences  can- 
not usually  be  traced.  Sanger  observed  a  leukemic  infant  born  of  a 
mother  who  was  healthy  and  remained  so.  On  the  other  hand,  many 
leukemic  women  have  given  birth  to  healthy  children.  The  influence 
of  direct  heredity  is  rare.  Casati  cited  the  case  of  a  girl  of  10  years 
whose  father  and  grandmother  were  leukemic,  while  Cameron  observed 
a  case  in  a  woman  whose  grandmother,  mother,  brother,  and  two 
children  were  leukemic.  Collateral  heredity,  the  aifection  of  brothers 
and  sisters,  has  been  frequently  observed.  (Nanny n,  Duret  and 
Vaquez,  Senator,  Ortner,  Casali,  Greene,  Eichhorst,  Bernier.) 

Trauma  has  been  demonstrated  to  be  a  direct  exciting  cause  of  leu- 
kemia in  a  large  number  of  authentic  cases.  The  traumatism  has  been 
applied  directly  to  the  spleen  (Velpeau,  Wallace,  Mosler,  Grawitz, 
Ebstein),  or  to  the  bones  (Virchow,  Grawitz,  Mursick)  in  which  case 
the  myelogenous  type  commonly  develops.  The  traumatism  may  con- 
sist in  general  concussion.  Preexisting  leukemia  was  thus  rendered 
rapidly  fatal  in  a  case  of  Greime's. 

The  significance  of  the  alleged  cases  of  leukemia  following  splenectomy 
will  be  considered  under  that  topic. 

Intestinal  intoxication  has  been  urged  as  the  exciting  cause  of  leu- 
kemia by  Vehsemeyer  who  believes  that  the  failure  of  conversion  of 
peptone  into  harmless  albumens  of  the  blood  is  the  important  causal 
factor  in  the  disease.  This  theory  was  suggested  by  the  frequency  of 
gastro-intestinal  disturbances  and  lesions  in  leukemia,  and  by  some  ob- 
servations of  Kottnitz  which  indicated  that  in  leukemia  the  gastro-in- 
testinal mucosa  loses  to  some  extent  the  power  to  transform  peptones. 


202  LEUKEMIA. 

The  effects  of  bad  hygiene  have  been  traced  in  a  large  number  of 
cases  (Mosler),  but  no  social  position  nor  occupation  distinctly  predis- 
poses to  the  disease. 

Other  diseases  predisposing  to  or  directly  exciting  leukemia  have 
been  reported  as  follows  : 

Syphilis,  acquired  and  constitutional,  especially  in  children,  and  ex- 
citing usually  the  myelogenous  type  ;  by  Steinbrugge,  Frankel,  Mosler. 

Malaria,  either  acute  or  chronic  (Muller,^  Gowers,  Osier  (33  per- 
cent)). Of  150  cases  collected  by  Gowers,  a  history  of  previous 
malaria  was  obtained  in  39,  while  in  many  the  spleen  had  remained 
enlarged  after  the  malarial  attack.  The  disease  has  been  attributed  to 
diphtheria,  by  Orth,  and  to  typhoid  fever,  smallpox,  and  pneumonia, 
by  Gowers. 

Influenza  has  several  times  been  reported  as  leading  to  acute  or 
chronic  leukemia.     (Hinterberger,  Frankel,^  Litten.') 

Rachitis,  latent  tuberculosis,  and  hypertrophic  intestinal 
lymph-follicles  from  chronic  catarrh  (constitutio  lymphatica?) 
have  been  noted,  singly  or  combined,  in  many  cases  of  mixed  type  in 
children.     (Mosler.^) 

Stomatitis,  ulceration  of  gums  or  tonsils,  preceding  or  early  ac- 
companying leukemia,  have  been  reported  by  many  observers  (Ebstein, 
Hinterberger)  but  are  probably  secondary  lesions. 

The  transformation  of  pernicious  anemia  into  leukemia  has  been  re- 
ported in  several  cases.  (Waldstein,  Litten,^  Masius  and  Francotte, 
Leube  and  Fleischner,  Musser.)  It  does  not  appear,  however,  that 
any  of  these  cases  indicate  a  relation  between  progressive  pernicious 
anemia  and  leukemia.  They  seem  to  the  writer  to  be  cases  of  leu- 
kemia in  which  there  was  a  temporary  reduction  in  leucocytes  at  the 
time  of  first  observation,  or  instances  of  marked  terminal  leucocytosis. 
The  case  of  Masius  and  Francotte,  in  a  patient  suffering  from  anchy- 
lostomiasis  indicates  that  severe  secondary  anemia  may  predispose  to 
leukemia.  An  apparently  genuine  instance  of  transformation  of 
pseudo-leukemia  into  acute  leukemia  is  reported  by  Mosler,^  and  Troje 
has  maintained  that  pseudo-leukemia  is  pathologically  a  forerunner  of 
leukemia. 

The  genuineness  of  many  reported  cases  of  leukemia  following  in- 
fectious diseases,  splenectomy,  childbirth,  anemia,  etc.,  has  been  seri- 
ously doubted,  and  it  has  been  agreed  on  all  hands  that  spurious  cases 
have  crept  into  the  literature,  especially  before  the  general  employ- 
ment of  Ehrlich's  methods  and  criteria.  The  recent  demonstration  of 
numerous  myelocytes  or  lymphocytes  in  inflammatory  leucocytosis 
(Engel,  the  writer,  etc.),  the  extreme  leucocytosis  (1-2),  observed  by 
Schede  and  Stahl  in  osteomyelitis,  and  Musser's  observation  of  a  pro- 
portion of  one  whijte  to  four  red  cells  in  pernicious  anemia,  render  it 
obvious  that  the  diagnosis  of  acute  leukemia  in  the  absence  of  micro- 
scopical examination  of  the  marrow,  is  often  a  hazardous  undertaking. 

Infectious  Origin. — The  chief  ground  for  a  belief  in  the  infectious 
nature  of  leukemia  is  found  in  the  rapidly  fatal  course  of  some  acute 


ETIOLOGY.  203 

cases  and  their  striking  clinical  resemblance  to  other  undoubted  infec- 
tious diseases.  Actual  contagiousness  is  suggested  by  the  report  by 
Obrastzow  of  an  acute  case  developing  in  a  hospital  attendant  six 
weeks  after  nursing  another  fatal  acute  case  of  the  myelogenous  type. 
Biological  studies  of  leukemic  blood  have  led  to  the  reported  demon- 
stration of  bacteria  and  of  other  micro-organisms  of  undetermined 
nature. 

Bacteria. — Kelsch  and  Vaillarcl  squeezed  drops  of  blood  from  the 
fingers  and  isolated  therefrom  a  diplo-bacillus  which  was  pathogenic  for 
mice.  The  same  bacilli  appeared  in  the  vessels  of  the  tumors.  Pawlowsky 
claims  to  have  found  one  and  the  same  bacillus  in  six  cases,  sometimes  in  the 
blood,  or  in  the  viscera,  especially  in  the  liver.  In  the  blood  they  were 
found  mostly  in  the  plasma.  In  cultures  on  glycerin  agar  the  bacillus  pro- 
duced a  somewhat  characteristic  growth.  Injected  into  rabbits  this  micro- 
organism could  be  identified  morphologically  iii  the  blood  for  several  weeks, 
but  no  symptoms  of  leukemia  were  produced.  Although  Pawlowsky  believed 
he  had  discovered  a  specific  microbe  in  the  disease,  he  has  not  yet  verified 
his  results.  Bonardi  obtained  cultures  of  Stcqihylococcus  pyogenes  aureus  and 
albus  from  the  blood  of"  two  cases  of  splenic  leukemia. 

Inoculations. — Mosler  and  Westphal  injected  leukemic  blood  into  dogs  and 
rabbits  with  negative  results.  Bollinger  with  the  blood,  and  Gilbert,  Cadiot 
and  Roger,  with  the  leukemic  tissues  of  diseased  dogs,  failed  to  produce  any 
significant  eflects  by  injections  into  healthy  animals. 

The  injection  of  leukemic  blood  and  of  the  fresh  juice  of  the  spleen  into 
various  animals  was  without  results  in  the  hands  of  Mo-sler  and  Westphal, 
Bollinger,  Nette,  Eichenbush,  and  Muller.'*  Nette  injected  defibrinated 
blood  under  the  skin,  into  the  peritoneum,  and  into  the  veins  of  the  ear, 
epigastrium,  and  marrow,  with  negative  results.  The  juice  of  leukemic 
nodes  was  injected  into  animals  without  eiFect  by  Troje,  Litten,  and  Gilbert. 
Negative  cultures  of  blood  were  obtained  in  acute  cases  by  Ebstein,  Roux, 
Westphal  and  Mosler,  Guttmann,  Mayet,  Eichhorst,i  Pfeiffer,  Litten,  and 
Sittmann. 

Micro-organisms  of  undetermined  nature  have  been  described  in  the 
blood,  or  in  the  leucocytes,  or  in  metastatic  deposits,  or  in  cultures,  by 
Klebs,2  McGillavry,  Osterwald,  Mayet, 2  Roux,  Bramwell,  Fermi,  and 
Klein. 

None  of  these  writers  has  been  able  to  follow  up  his  observations. 

The  observations  of  Mannaberg  and  of  Lowit  ^  point  to  the  possible 
existence  of  protozoa  in  leukemic  blood. 

In  8  percent  of  the  lymphocytes  of  a  case  of  lymphatic  leukemia  Manna- 
berg found  hyaline  bodies  1-4  /^i  in  diameter,  exhibiting  ameboid  activity 
such  as  is  seen  in  the  quartan  malarial  parasites.  They  failed  to  exhibit  a 
nucleus  by  Romanowsky's  stain,  but  after  fixation  in  Hermann's  fluid  they 
stained  well  with  saffranin. 

In  the  peripheral  blood  and  viscera  in  mj'^elemia  Lowit  has  recently  re- 
ported the  discovery  of  an  ameba  which  he  classes  Avith  the  sporozoa  and 
terms  hemameba  leukemise  magna.  In  lymphemia  he  finds  another  somewhat 
different  ameba,  hemameba  leukemia;  I'ivax.  which  is  scarce  in  the  blood,  but 
abundant  in  the  viscera.  In  some  mixed  cases  both  amebse  were  present, 
and  they  were  also  seen  in  pseudo-leukemia  and  in  v.  Jaksch's  anemia. 
Lowit  has  found  the  same  amebpe  in  leukemic  animals  and  claims  to  have 
transferred  the  disease  from  one  animal  to  another. 

The  method  employed  by  Lowit  in  the  demonstration  of  the  parasite  of 
leukemia  is  as  follows  : 


204  LEUKEMIA. 

The  blood  smeared  in  a  thin  layer  is  heated  1-2  hours  at  110°-120°  C. 
and  stained  one-half  hour  in  a  concentrated  watery  solution  of  thioniu.  After 
thorough  washing  in  tap-water,  and  drying  in  air,  the  specimen  is  laid  for 
10-20  seconds  in  solution  of  iodine  (I,  1;  KI,  2  ;  Aq.  dest.  300),  again  washed, 
dried,  and  mounted  in  balsam.  The  parasite  in  its  various  stages  then 
appears  green  or  olive  green,  or  greenish  black,  the  basophile  granules  and 
degenerated  products  of  nucleus  and  cell  body  bluish  red  or  brownish  red, 
the  protoplasm  of  leucocytes  and  their  granules  yellowish  or  yellowish 
brown.  The  blood  smear  must  be  thin.  The  solution  of  thionin  should  be 
several  weeks  or  months  old,  long  exposed  to  sunlight,  and  preferably  con- 
taining a  considerable  growth  of  micro-organisms  which  seem  to  assist  in 
"ripening"  the  stain.  In  the  absence  of  an  old  solution  good  results  may 
be  obtained  with  a  mixture  of  the  thionin  solution,  30  ;  Loeffler's  methylene- 
blue,  15  ;  but  the  green  color  of  the  parasites  may  be  obscured  by  a  diffuse 
dark  stain  from  the  methylene- blue.  The  fading  which  ordinary  prepara- 
tions suffer  within  a  few  days  may  be  avoided  by  mounting  the  specimen  in 
balsam  which  has  been  mixed  with  a  solution  of  iodine  in  xylol  until  the 
balsam  is  of  light  yellowish  ccSlor. 

Lowit  regards  the  greenish  stain  produced  by  his  method  as  the  specific 
reaction  of  the  parasite,  and  finds  reason  to  believe  that  this  color  is  assumed 
by  a  substance  identical  with  or  closely  related  to  cellulose. 

Turk  believes  that  the  hemameba  of  Lowit  is  an  artifact  resulting  from 
the  partial  solution  and  deformation  of  mast-cell  granules  by  the  action  of 
watery  dj^es.  He  claims  to  have  found  similar  bodies  in  the  blood  of  healthy 
men  and  rabbits. 

Pathological  Changes  in  the  Viscera. — Only  the  portions  of  this 
extensive  subject  will  here  be  considered  which  bear  upon  the  patho- 
genesis of  the  disease. 

Marrow. — In  the  early  stages  of  the  leukemic  process  the  lymphoid 
marrow  exhibits  a  slightly  lighter  color  and  greater  consistence  than 
is  normal.  This  change  results  from  a  cellular  hyperplasia,  which 
obliterates  blood  sinuses,  diminishes  the  blood  content,  and  causes 
atrophy  of  fat  cells.  With  this  cellular  hyperplasia  of  the  marrow  of 
ribs,  vertebrse,  etc.,  there  is  an  extension  of  lymphoid  marrow  through- 
out the  shafts  of  long  bones  where  also  the  marrow  appears  firm  and 
light  colored.  While  in  early  stages  the  marrow  may  retain  a  fleshy 
tint,  in  advanced  cases  it  is  almost  invariably  very  light  colored  and 
firm.  In  some  advanced  cases  sclerotic  and  degenerative  processes 
may  follow  the  cellular  hyperplasia,  the  writer  having  seen  consider- 
able areas  of  connective  tissue  and  foci  of  mucoid  degeneration  in  the 
marrow  of  old  cases. 

In  acute  leukemia  the  marrow  may  be  strikingly  puriform  in  ap- 
pearance, though  invariably  less  diffluent  than  pus.  In  one  case  of  the 
writer's  this  resemblance  to  pus  was  so  marked  as  to  require  micro- 
scopical section  before  the  hyperplastic  marrow  of  the  femur  could  be 
positively  identified. 

In  myelogenous  leukemia  the  affection  of  the  marrow  has  in  all  un- 
doubted cases  been  distinct  and  if  Litten's  case  can  be  accepted,  as  is 
doubtful,  the  leukemic  process  may  be  limited  to  the  marrow.  Leube 
and  Fleischer  (1881)  attempted  to  prove  the  contrary  by  a  case  show- 
ing a  marked  leucocytosis  (1-1'2)  and  dying  of  progressive  gangrene, 
in  which  no  hyperplasia  of  the  marrow  was  found.     In   lymphatic 


PATHOLOGICAL   CHANGES  IN   VISCERA.  205 

leukemia  it  was  early  shown  that  the  marrow  may  be  very  slightly  or 
not  all  involved  (Heuck/  Fleischer,  Penzoldt),  although  in  many  such 
cases  the  usual  extensive  hyperplasia  is  observed  (Muller). 

Hirschlaff  has  recently  reported  two  obscure  cases,  one  of  which  appears 
to  have  been  an  example  of  pure  splenic  leukemia  Avith  peculiar  blood 
changes.  In  the  other  no  distinct  leukemic  lesions  were  found  in  the  vis- 
cera. Similar  negative  results  at  autopsy  have  been  recorded  by  Eichhorst  - 
and  by  Ambros. 

The  microscopical  examination  of  the  marrow  in  leukemia  shows 
that  the  hyperplasia  affects  the  variety  of  cells  seen  most  abundantly 
in  the  blood.  In  myelogenous  leukemia  these  cells  are  largely  the  neu- 
trophile  myelocytes  which  are  found  in  very  excessive  numbers,  of 
very  large  size,  and  in  mitotic  division,  or  in  various  stages  of  degener- 
ation. In  the  same  cases  also  there  is  almost  invariably  an  excessive 
number  of  large  mononuclear  hyaline  cells.  Eosins  and  giant  cells 
may  long  persist,  but  do  not  appear  to  take  a  prominent  part  in  the 
hyperplasia. 

In  pure  lymphatic  leukemia  the  lymphocytes  alone  are  found  in  the 
hyperplastic  areas  (Muller^)  and  eosinophile  and  neutrophile  cells  are 
very  scarce,  but  there  appear  to  be  all  grades  between  the  pure  lym- 
phatic and  myelogenous  types  of  leukemia,  in  which  the  changes  in  the 
marrow  correspond  in  general  to  those  in  the  blood. 

It  is  held  by  some  (Ponfick,  Hosier, 2  Muller  2)  that  the  leukemic  process 
may  at  one  period  of  its  cour.se  affect  principally  the  lymphoid  structures, 
at  another  the  marrow,  so  that  the  blood  may  at  one  time  exhibit  the 
changes  of  lymphatic,  at  another  those  of  myelogenous  leukemia.  Fleischer 
and  Penzoldt's  case  illustrates  such  a  variation. 

The  red  blood  cells  of  the  marrow  are  not  greatly  affected  in  the 
early  stages  of  leukemia,  as  is  indicated  by  the  frequent  absence  of 
marked  anemia,  although  in  very  cellular  areas  they  are  diminished  in 
number  from  the  first.  Later,  in  chronic  myelogenous  cases  the  same 
changes  are  seen  as  in  pernicious  anemia,  but  the  excessive  numbers  of 
megaloblasts  are  seldom  so  prominent.  In  some  acute  cases,  especially 
those  of  lymphatic  type,  the  writer  has  seen  almost  entire  absence  of 
nucleated  red  cells  in  considerable  sections. 

The  distribution  of  the  lesion  in  the  marrow  of  lymphatic  leukemia  is 
often  very  irregular.  In  an  acute  case  the  writer  has  found  entirely 
normal  structures  in  the  ribs  and  femur  while  the  usual  hyperplasia 
was  present  in  the  bodies  of  vertebrae.  Moreover  the  lesion,  at  least 
in  its  early  stages,  appears  to  be  focal  rather  than  diffuse.  These  pe- 
culiarities render  it  essential  that  very  complete  examinations  should 
be  made  before  it  can  be  positively  claimed  that  leukemia  can  exist 
without  lesions  in  the  marrow. 

Hirschlaff,  Kormoczi,  and  Pappenheim  report  cases  of  lymphatic  leu- 
kemia in  which  the  lesion  was  exclusively  in  the  marrow,  and  Pappenheim 
holds  that  lymphemia  is  always  of  myelogenous  origin.  This  view  is  apjtar- 
ently  disproved  by  the  case  of  Rosenfeld's  in  which  no  change  was  dis- 
covered in  the  marrow. 


206  LEUKEMIA. 

Liver. — The  enlargement  of  this  organ  is  usually  referable  to  the 
presence  of  numerous  metastatic  growths,  which  follow  the  course  of 
development  described  for  all  secondary  leukemic  deposits,  and  to  in- 
filtration of  capillaries  with  proliferating  leucocytes.  In  myelogenous 
leukemia  the  liver  is  seldom  free  from  such  deposits,  but  in  the  lym- 
phatic type  the  infiltration  is  usually  limited  to  the  portal  canals  aud 
intralobular  capillaries,  although  it  may  produce  circumscribed  tumors. 

It  is  of  great  interest  to  note  that  the  liver  in  myelogenous  leukemia 
gives  evidence  of  having  resumed  its  embryonal  function  of  developing 
red  cells.  Neumann  and  Heuck  first  called  attention  to  the  presence 
of  considerable  numbers  of  nucleated  red  cells  in  the  hepatic  capillaries. 
In  Heuck's  case  they  were  distinctly  more  abundant  than  in  the  gen- 
eral circulation.  The  resemblance  of  the  leukemic  to  the  embryonal 
liver  is  completed  in  the  presence  of  mitotic  leucocytes  aud  giant  cells, 
as  described  by  Neumann,^  Muller,  and  others. 

Spleen. — The  pathological  process  in  the  spleen  consists  in  hyper- 
plasia of  large  and  small  mononuclear  cells.  These  cells  appear  in 
excessive  numbers  throughout  the  pulp  cords,  while  the  limits  of  the 
Malpighian  bodies  become  less  defined.  As  a  result  of  this  cellular 
hyperplasia  the  sinuses  are  choked  with  cells,  and  hemorrhages,  in- 
farcts, degeneration,  and  necroses  occur,  which  lead  to  a  variety  of 
gross  appearances  in  the  enlarged  organ. 

Regarding  the  exact  nature  of  the  cellular  processes  it  has  been 
shown  that  in  myelogenous  leukemia,  while  the  majority  of  the  cells  in 
the  spleen  are  hyaline,  yet  neutrophile  myelocytes  occur  in  moderate 
numbers.  These  are  generally  regarded  as  derivatives  of  the  marrow 
brought  by  the  blood  stream,  although  Muller  has  once  seen  mitosis 
in  a  splenic  myelocyte.  Numerous  giant  cells  are  sometimes  found, 
which  Muller  regards  as  originating  in  situ.  For  the  increased  num- 
ber of  large  and  small  lymphocytes  the  chief  mode  of  origin  must  be 
mitotic  division  in  situ,  especially  in  the  Malpighian  bodies,  as  has 
been  demonstrated  by  Muller.  Along  with  this  excess  of  colorless 
cells,  the  organ  commonly  contains  an  excess  of  blood,  and  the  usual 
process  of  destruction  of  red  cells  may  everywhere  be  observed. 

Nucleated  red  cells  are  visible  in  smears  of  splenic  pulp  in  most 
cases  of  myelogenous  leukemia.  The  writer  has  been  unable  to  con- 
vince himself  that  they  are  more  numerous  than  in  the  general  circu- 
lation, or  if  slightly  more  numerous,  that  they  are  not  mechanically 
sifted  from  the  blood.  Heuck,  however,  found  them  in  the  splenic 
smears  when  they  were  absent  in  the  general  circulation  and  concluded 
that  the  spleen  in  leukemia  may  resume  its  embryonal  function  of 
developing  red  cells. 

Following  the  stages  of  acute  hyperplasia,  comes  a  later  period 
marked  by  continuous  inci'ease  in  the  size  of  the  organ,  and  great  in- 
crease in  consistency,  owing  to  fibroid  changes  beginning  in  the 
trabecula  and  often  extending  diifusely  throughout  the  pulp.  In  such 
stages  the  cellular  content  is  comparatively  diminished  without  any 
apparent  effect  upon  the  character  of  the  blood. 


PATHOLOGICAL  CHANGES  IN   VISCERA.  207 

In  lymphatic  leukemia  the  same  course  of  events  is  observed,  but 
the  new  cells  are  limited  to  the  large  and  small  lymphocytes.  In  this 
form  of  the  disease  the  lymph  follicles  are  apt  to  be  enlarged. 

The  general  appearance  of  sections  of  the  spleen  in  myelogenous 
leukemia,  the  congestion,  the  indiscriminate  filliug  of  sinuses  with  red 
and  white  cells,  the  destruction  of  Malpighian  bodies,  the  prominence 
of  fibroid  changes,  and  the  usual  absence  of  areas  of  distinct  leukemic 
deposits,  strongly  indicate  that  the  enlargement  of  this  organ  results 
largely  from  mechanical  sifting  of  red  and  ichite  cells  from  the  circulation 
and  subsequent  inflammatory  changes.  In  lymphatic  leukemia,  how- 
ever, the  proliferation  of  lymphocytes  is  usually  very  marked  and  the 
Malpighian  bodies  must  be  considered  one  of  the  most  important  pri- 
mary seats  of  the  disease.  In  some  cases  it  may  perhaps  be  the  ex- 
clusive seat  of  the  primary  lesion.     (Cf.  Hirschlaif,  Rosenfeld.) 

Lymph  Nodes  and  Other  Lymphatic  Structures. — Swelling  of  the 
lymph  nodes  is  one  of  the  earliest  of  observed  symptoms,  having  in 
some  lympathic  cases  preceded  all  other  signs  for  some  months.  They 
may  reach  a  considerable  size,  that  of  a  hen's  egg,  but  seldom  become 
excessively  hirge.  Their  capsules  are  almost  invariably  intact  unless 
ulceration  occurs.  The  stage  of  cellular  hyperplasia  is  succeeded,  here 
as  in  the  spleen,  by  one  of  fibrosis  with  diminution  in  the  number  of 
cells. 

In  myelogenous  leukemia  the  smears  of  lymph  nodes  yield  almost 
the  same  appearances  as  those  of  the  spleen,  except  for  a  relative  ex- 
cess of  lymphocytes.  Neutrophile  myelocytes  are  scanty,  but  here 
again  Muller  has  found  mitosis  in  myelocytes.  On  section,  the  out- 
lines of  the  lymph  follicles  are  lost,  and  the  tissue  consists  of  a  diffuse 
mass  of  mononuclear  cells,  large  and  small,  resembling  lymphocytes 
and  often  seen  in  mitotic  division.  In  some  cases  distinct  prolifera- 
tion zones  appear  in  small  foci  where  the  multiplication  of  leucocytes 
is  very  active. 

Although  the  sinuses  are  usually  choked  and  indistinguishable,  yet, 
according  to  Birch-Hirshfeld,  most  of  the  lymph  nodes  of  leukemia  differ 
from  those  of  j^seudo-leukemia,  in  the  fact  that  substances  injected  into  the 
capsules  pass  through  the  leukemic  node  into  the  efferent  vessel,  but  in 
pseudo-leukemia  the  enlarged  nodes  are  impervious.  The  writer  has  been 
unable  to  find  in  literature,  or  in  sections  and  smears  of  nodes  from 
his  own  cases,  any  constant  microscopical  differences  distinguishing  the 
lymphatic  from  the  myelogenous  type  of  the  disease.  In  the  former 
the  small  lymphocytes  are  rather  more  numerous,  and  of  course  the 
hyperplasia  is  usually  much  more  marked. 

In  addition  to  the  lymph  nodes,  spleen,  and  marrow,  all  preexisting 
lymphoid  structures  may  become  hyperplastic,  especially  in  lymphatic 
leukemia,  and  new  growths  of  lymphoid  tissue  have  been  found  of 
nearly  universal  distribution.  From  all  of  these  localities  new  leuco- 
cytes are  undoubtedly  contributed  to  the  circulation. 

Character  of  Metastatic  Deposits. — Although  Rindfleisch,  Cornil  and 
Ranvier,  and  Zeigler,  held  that  leukemic  deposts  arise  by  mechanical 


208  LEUKEMIA. 

lodgment  of  increasing  numbers  of  leucocytes  from  the  blood,  Virchow 
early  maintained  that  these  deposits  arise  in  situ.  It  has  since  been 
shown  that  \Yhile  the  early  minute  collections  of  cells  are  ivhiie  cell 
thrombi,  the  further  growth  of  these  masses  takes  place  principally  by 
mitotic  division  of  these  cells.  (Bizzozero,  Muller,  and  Neumann.) 
Bizzozero  has  pointed  out  that  the  structure  of  these  metastases  closely 
resembles  that  of  Ivmph  nodes  with  reticulum  and  sinuses,  and  is  not 
at  all  that  of  an  indiscriminate  deposit  of  blood  cells.  He  found  in 
such  deposits  quite  as  many  mitotic  nuclei  as  in  similar  nodules  of 
metastatic  carcinoma.  Leukemic  deposits  must  therefore  be  regarded 
as  conforming  in  many  important  respects  to  the  laws  governing  meta- 
static neoplasms. 

The  lymph  nodes  and  spleen  when  affected  exhibit  an  hyperplasia 
of  the  lymphocytes,  which  choke  the  sinuses,  obliterate  the  follicles, 
and  cause  an  overflow  of  these  cells  into  the  blood  and  probably  also 
into  the  lymph  stream.  In  lymphatic  leukemia  the  new  cells  are  of 
small  size ;  in  myelemia  the  cells  are  either  of  small  size  or  larger,  and 
with  a  distant  mass  of  protoplasm  about  the  nuclei.  The  writer  has 
made  several  attempts  to  demonstrate  neutrophile  granules  in  the  cells 
of  the  lymph  nodes  in  myelogenous  leukemia  but  without  success. 

In  chronic  cases,  the  stage  of  hyperplasia  is  regularly  followed  by 
one  of  fibrosis,  which  in  the  spleen  greatly  increases  the  size  and  con- 
sistence of  the  organ. 

Pathogenesis. — The  conclusions  regarding  the  pathogenesis  of  leu- 
kemia which  seem  to  be  warranted  from  the  foregoing  review  of  the 
etiology  and  pathological  anatomy  of  the  disease  are  to  a  large  extent 
those  formulated  by  Virchow  and  Neumann,  whose  original  ideas  have 
been  partially  readjusted  from  time  to  time  to  suit  newly  acquired 
facts. 

Leukemia  must  now  be  considered  a  primary  disease  of  the  blood- 
producing  organs,  principally  or  exclusively  affecting  the  marrow  or 
the  lymphoid  structures.  The  essential  process  consists  in  an  excessive 
hyperplasia  of  the  myelocytes  or  lymphocytes,  or  both  varieties  of 
blood  cells,  with  secondary  increase  of  leucocytes  in  the  blood,  secon- 
dary lesions  in  the  blood-forming  and  other  organs,  and  leading  even- 
tually to  disturbances  in  the  production  of  red  cells  and  to  pernicious 
anemia.  In  the  myelogenous  type,  the  marrow  and  the  neutrophile 
myelocytes  are  chiefly  affected  and  the  development  of  red  cells  is  soon 
disturbed.  In  lymphatic  leukemia  the  lymphoid  structures  (lymph 
nodes,  spleen,  lymph  cells  of  marrow)  are  almost  exclusively  affected 
and  red  cell  formation  is  less  early  disturbed.  In  many  cases  the  type 
of  the  disease  is  mixed,  and  it  appears  probable  that  the  disease  may 
principally  affect  one  organ  (the  marrow)  at  one  time,  and  another 
organ  (the  lymph  nodes)  at  a  later  stage.  In  either  case  the  spleen  is 
affected  secondarily  by  mechanical  lodgment  of  leucocytes  and  red 
cells,  probably  also  by  toxic  chemical  influences.  In  lymphatic  leu- 
kemia the  spleen  may  take  active  part  in  the  initial  process  and  furnish 
many  new  lymphocytes  to  the  blood,  but  in  myelogenous  leukemia  its 


PATHOGENESIS.  209 

behavior  is  largely  passive,  and  it  seldom  becomes  the  seat  of  true  leu- 
kemic new  growths  but  may  as  usual  furnish  lymphocytes  to  the  blood. 
Pure  myelogenous  leukemia  appears  not  to  have  been  demonstrated, 
unless  in  some  very  acute  cases,  or  in  some  reported  cases  of  lymphemia. 

The  importance  of  jiroJiferation  of  leucocytes  in  the  circulation  has 
been  maintained  especially  by  Biesiadecki  and  Lowit,^  who  believe 
that  leukemia  is  a  primary  disease  of  the  blood.  While  nearly  all  ex- 
perienced observers  agree  that  leucocytes  multiply  to  some  extent  in 
the  circulation,  there  is  almost  equal  agreement  that  the  extent  of 
mitotic  division  in  the  blood  is  inconsiderable  compared  with  that  in 
the  viscera. 

The  leukemic  deposits  of  the  viscera  develop  by  proliferation  of 
original  thrombi  of  leucocytes,  which  under  favorable  conditions  un- 
dergo active  mitotic  division,  develop  a  supporting  stroma  and  behave 
in  essential  particulars  like  true  neoplasms,  while  probably  continuing 
to  furnish  new  leucocytes  to  the  blood. 

The  red  cells  during  the  early  stages  of  myelemia  suffer  from  the 
disturbances  of  development  such  as  exist  in  chlorosis.  In  later  stages 
red  cell  production  reverts  to  the  embryonal  megaloblastic  type,  mitotic 
megaloblasts  are  seen  in  the  marrow,  spleen,  and  liver,  and  the  changes 
of  pernicious  anemia  are  established  in  the  blood. 

The  theory  that  polynuclear  ueutrophile  leucocytes  are  developed  from 
lymphocytes  met  an  insurmountable  difficulty  in  the  blood  of  lymphatic 
leukemia,  and  gave  birth  to  a  prominent  theory  of  the  pathogenesis  of  the 
disease  now  maintained  chiefly  by  Lowit. 

Lowit,  representing  the  views  of  most  of  the  early  observers,  believes  that 
the  essential  process  in  leukemia  is  a  failure  of  full  development  of  mononu- 
clear cells  (lymphocytes,  myelocytes).  This  theory,  the  discussion  of  which 
has  cumbered  the  literature  of  the  subject  to  an  enormous  extent,  becomes 
untenable  since  the  lymphocytes  appear  to  have  no  developmental  relation 
to  ueutrophile  cells. 

The  partial  resemblance  of  leukemia  to  a  neoplasm  affecting  the 
lymph  nodes,  spleen,  marrow,  or  blood,  was  early  recognized  and  this 
theory  of  origin  has  been  discussed  by  most  writers  and  openly  main- 
tained by  Kottman,  Bard,  Herzfeld,  and  lately  by  Gilbert,  who  com- 
pares lymphemia  to  a  sarcoma  affecting  lymphocytes. 

To  what  extent  the  origin  and  course  of  leukemia  follows  the  laws 
known  to  govern  neoplasms  is  an  interesting  inquiry  which  cannot  here 
be  pursued  at  length,  but  which  may  well  be  kept  in  mind.  Accord- 
ing to  such  a  theory  it  is  necessary  to  suppose  that  lymphatic  leukemia 
is  a  tumor  originating  in  the  lymphocytes,  myelemia  a  tumor  affecting 
myelocytes. 

There  are,  however,  other  tumors  affecting  lymphocytes,  the  lympho- 
sarcomata,  which  behave  in  a  very  different  manner  from  lymphemia, 
in  growth  and  especially  in  their  metastatic  characters.  It  seems  not 
impossible,  however,  that  all  these  differences  may  be  referred  to  the 
involvement  of  the  blood  in  the  latter  case  and  that  all  gradations  ex- 
ist between  lymphatic  leukemia  through  pseudo-leukemia,  to  genuine 
14 


210  LEUKEMIA. 

lympho-sarcoma.     The  cases  of  lymphemia  arising  in  the  course  of 
lympho-sarcoma  are  here  of  great  interest. 

Changes  in  the  Blood. 

The  bulk  of  blood  is  apparently  little  altered  by  the  uncomplicated 
leukemic  process  but  in  autopsies  on  chronic  cases,  the  same  diminu- 
tion in  the  total  quantity  of  blood  may  be  noted  as  in  pernicious 
anemia,  and  from  the  same  cause. 

The  color  of  the  blood  may  in  well-marked  cases  be  entirely  normal, 
as  anemia  is  of  slow  progress.  Usually  it  is  slightly  lighter  in  color 
and  more  fluid,  owing  to  pronounced  anemia  and  great  excess  of  leuco- 
cytes. The  exuded  drop  has  been  described  as  lymphoid  or  puriform, 
but  when  properly  expressed,  blood  of  such  character  must  be  ex- 
tremely rare.  When  the  red  cells  are  below  one  million  and  the  leu- 
cocytes almost  equally  numerous  the  blood  drop  still  resembles  blood, 
though  of  very  light  color.  When  obtained  in  bulk  at  autopsy  the 
blood  coagulates  slowly,  the  red  cells  settle  to  the  bottom  followed  by 
a  characteristic  thick  layer  of  leucocytes  and  fibrin,  while  the  very  clear 
serum  floats  above.  In  the  cadaver  pure  deposits  of  leucocytes  re- 
sembling abscesses  may  be  found  in  various  situations  often  in  the 
heart  and  pulmonary  vessels. 

The  coagulability  is  greatly  diminished  and  may  be  entirely  lost,  but 
less  often  than  in  fatal  pernicious  anemia. 

To  the  touch,  the  blood  may  have  a  cohesive  mucous  quality,  as 
noted  by  Grawitz. 

When  leukemic  blood  is  smeared  and  dried  on  a  glass  slide  it  ex- 
hibits a  peculiar  granular  opaque  appearance  which  is  readily  identi- 
fied as  belonging  to  a  great  excess  of  leucocytes. 

The  Red  Cells. — In  average  chronic  cases  the  red  cells  are  usually 
reduced  to  2-3  millions,  falling  to  one  million  or  lower  in  fatal  cases, 
but  not  usually  reaching  the  extreme  reductions  seen  in  pernicious 
anemia.  On  the  other  hand  Cabot  reports  a  case  with  over  5  million 
red  cells,  134,000  white,  Hb  78  percent.  At  death,  the  numbers  of 
red  cells  depend  upon  the  presence  or  absence  of  hemorrhage,  and 
upon  the  length  and  character  of  the  disease.  There  are  no  marked 
differences  in  the  grade  of  anemia  in  lymphatic  and  myelogenous  leu- 
kemia. 

Morphological  changes  in  the  red  cells  are  invariably  present.  In  the 
average  chronic  case  the  uniform  loss  of  Hb  in  red  cells  showing  nor- 
mal rouleaux  and  very  uniform  size  and  shape,  with  a  rather  free  ad- 
mixture of  normoblasts,  gives  to  the  stained  blood  smear  a  very 
peculiar  and  almost  pathognomonic  character.  Possibly  the  abundance 
of  leucocytes  controls  the  movements  of  the  red  cells  in  the  smearing 
process,  but  from  some  cause  the  appearance  of  the  red  cells  in  stained 
specimens  of  leukemic  blood  is  very  characteristic.  (See  Plate  VII.) 
At  this  early  stage  the  normoblasts  are  frequently  present  in  greater 
numbers  than  in  any  other  similar  condition. 


PLA  1  h.    VII, 


^  •  •         • 

•  •  • 


'.*•>-•  .    •  ♦. 


r^'.V^t-'  .  * 


.t'»"  'rX- •;>♦/.•/ 10 


w 


Myelogenous    Leukemia.     (Triacid   Stain.) 

Figs.  I.  Normal-sized  red  cells,  deficient  in  Hb. 

Figs.  2.  Pear-shaped  poikilocyte. 

Fig.  3.  Normoblast. 

Fig.  4.  Myelocytes  (Ehrlich's). 

Fig.  5.  Myelocyte  (Cornil's). 

Fig.  6.  Myelocyte  (eosinopbile). 

Fig.  7.  Eosinopbile  leucocyte  (normal). 

Fig.  8.  Blood  plates. 

Fig.  9.  Lympbocyte. 

Fig.  10.  Polynuclear  leucocyte,  nucleus  subdivided. 


THE  LEUCOCYTES.  211 

Later,  the  red  cells  begin  to  show  the  changes  of  more  severe  chlo- 
rotic  anemia,  differences  in  size  and  shape  appearing,  degenerative 
changes  occurring  with  greater  frequency  and  extent,  till  in  many  old 
severe  cases,  the  features  of  pernicious  anemia  are  fully  established. 
Even  in  such  stages,  however,  the  appearance  of  the  red  cells  usually 
differs  distinctly  from  that  of  pernicious  anemia,  in  the  more  uniform 
loss  of  Hb,  and  in  the  larger  number  of  nucleated  red  cells  among 
which  a  few  are  almost  invariably  normoblasts.  Mitotic  nucleated 
red  cells  are  rare.  In  most  other  respects  the  same  changes  are  seen 
as  in  pernicious  anemia. 

Hemoglobin. — Estimates  of  Hb  in  leukemia  are  at  present  some- 
what unsatisfactory,  owing  to  the  opacity  produced  in  the  diluted 
blood  by  an  excess  of  leucocytes.  In  the  early  stages  of  the  disease 
the  loss  of  Hb  follows  the  reduction  in  red  cells  as  in  chlorosis,  a 
diminution  being  demonstrable  at  times  before  any  change  in  the  num- 
ber of  red  cells,  and  the  Hb-index  remaining  about  .5-.6.  Later,  the 
estimates  are  untrustworthy,  but  the  Hb-index  probably  rises. 

The  Leucocytes. — The  white  cells  are  usually  so  much  increased 
as  to  leave  no  doubt,  from  their  numbers  alone,  as  to  the  nature  of  the 
disease.  In  cases  of  very  moderate  severity  there  are  usually  from 
100,000-200,000  leucocytes;  Cabot's  average  of  first  examinations  in 
39  cases  was  438,000.  Rarely  a  million  or  more  white  cells  are  pres- 
ent in  the  cubic  millimeter  of  expressed  blood,  but  it  appears  doubtful 
if  any  such  excessive  number  actually  exists  throughout  the  circula- 
tion . 

As  a  rule,  the, severity  of  the  general  condition  is  proportionate  to 
the  increase  of  leucocytes,  except  in  acute  leukemia,  when  the  num- 
bers of  leucocytes  may  not  exceed  that  of  inflammatory  leucocytosis. 

Variations  in  the  number  of  leucocytes  may  be  observed  at  differ- 
ent periods  of  the  day,  as  shown  by  Hayem,  who  found  122,500  at 
10  A.  M.,  235,000  at  4  P.  M.  of  the  same  day.  These  rapid  changes 
must  be  referred  largely  to  vaso-motor  disturbances  leading  to  unequal 
distribution  of  cells,  or  possibly  to  a  sudden,  but  temporary,  increase 
of  the  leucocytes  discharged  from  the  marrow.  Other  variations  in 
number  of  leucocytes  will  be  considered  under  the  course  of  the 
disease. 

Morphology  of  Leucocytes  in  Myelemia.  1.  Neutrophile  Myelo- 
cytes.— These  are  large  mononuclear  cells  with  neutrophile  granules. 
It  is  of  some  moment  to  distinguish  two  varieties  of  neutrophile 
myelocytes  in  leukemia. 

(a)  Cells  of  about  the  same  size  as  normal  polynuclear  leucocytes, 
with  well-staining,  central  nucleus,  as  described  by  Ehrlich  and  Uthe- 
man.  These  cells  are  abundantly  present  in  leukemic  blood  and  are 
generally  the  only  form  of  myelocyte  seen  in  secondary  anemia. 
(Plate  VII.,  Fig.  4.) 

(6)  Cornil  and  H.  F.  Muller  have  called  special  attention  to  the 
large  myelocyte  loith  pale  eccentric  nucleus.  This  cell  is  not  usually 
seen  except  in  leukemia  but  in  some  other  conditions,  especially  in  the 


212  LEUKEMIA. 

secondary  anemia  of  children,  it  may  appear  in  moderate  numbers. 
These  cells  have   frequently  been    seen  in  mitotic   division.     (Plate 

VII.,  Fig.  5.) 

As  first  shown  by  Mosler,  and  abundantly  verified  by  later  observers, 
the  presence  of  large  numbers  of  neutrophile  myelocytes  is  pathogno- 
monic of  leukemia.  In  28  cases  (chronic?),  Cabot  found  that  between 
20-60  percent  (average  35  percent)  of  all  leucocytes  present  were 
myelocytes.  With  the  extreme  leucocytosis  of  chronic  leukemia  there 
are  nearly  always  enough  myelocytes  present  to  establish  the  diagno- 
sis as  against  any  other  condition  that  has  yet  been  observed. 

In  acute,  myelogenous  leukemia,  however,  this  rule  may  fail  and  both 
the  numbers  and  j^roportions  of  myelocytes  may  not  exceed  those  seen  by 
En  gel  in  fatal  diphtheria. 

Of  recent  cases  of  acute  leukemia  in  which  the  type  of  the  disease  was 
satisfactorily  determined,  Frankel  (1895)  could  find  only  three  of  myeloge- 
nous type,  the  great  majority  being  of  the  lymphatic  variety.  In  1897  the 
writer  saw  three  cases  of  rapidly  fatal  leukemia,  verified  by  autopsies,  and 
all  of  the  myelogenous  type.  They  occurred  in  the  services  of  Drs.  Thom- 
son and  Delafield  at  Roosevelt  Hospital.  In  two  of  these  the  changes  in  the 
blood  were  from  the  first  observation  typical  of  the  condition  and  the  mar- 
row was  puriform,  while  the  spleen  and  lymph  nodes  were  but  slightly  af- 
fected. In  the  third  case,  on  the  first  examination,  with  a  leucocytosis  of 
ordinary  inflammatory  grade,  5  percent  of  the  cells  were  with  difiiculty 
recognized  as  myelocytes.  Eosinophile  myelocytes  and  normoblasts  were 
absent,  and  there  was  then  no  sufficient  ground  on  which  the  diagnosis  of 
leukemia  could  rest.  Later  the  leucocytosis  and  the  proportion  of  myelo- 
cytes increased  and  the  diagnosis  of  acute  leukemia,  made  with  reserve  just 
before  death,  was  fully  verified  at  autopsy. 

In  this  case,  on  account  of  the  small  number  and  indistinctness  of  the 
granules  in  the  myelocytes,  as  well  as  the  moderate  grade  of  leucocytosis, 
the  writer  did  not  feel  certain  of  the  diagnosis  until  after  the  microscopical 
examination  of  the  bone  marrow. 

Degenerative  Changes  in  Myelocytes. — The  myelocytes  of 
leukemia  are  usually  deficient,  and  may  be  entirely  lacking,  in  neutro- 
phile granules.  In  the  latter  case  they  are  indistinguishable  from 
large  lymphocytes  except  by  the  great  pallor  of  their  nuclei  (triacid 
stain).  Such  forms  occur  especially  in  acute  leukemia.  The  nuclei 
of  degenerating  myelocytes  may  undergo  hydropic  degeneration.  It 
is  then  practically  impossible  to  determine  the  origin  of  these  altered 
cells.  (Plate  IX.,  Figs.  1,  2.)  (Cf.  Grawitz,  p.  122.)  Some  very  small 
mononuclear  cells  with  neutrophile  granules  seen  in  leukemic  blood 
Ehrlich  regards  as  the  result  of  subdivision  of  polynuclear  leucocytes 
(neutrophile  pseudolymphocytes). 

In  the  fresh  condition  myelocytes  fail  to  exhibit  ameboid  motion,  a 
character  which  is  regarded  by  many  as  indicating  a  loss  of  further 
power  of  development. 

2.  Polynuclear  neutrophile  leucocytes  are  excessively  numerous  in 
myelocythemia  but  are  commonly  found  in  diminishing  proportions, 
though  in  increasing  numbers,  as  the  percentage  of  myelocytes  in- 
creases.    Cabot,  using  the  triacid  stain,  found  between  17—72  percent 


PLATE    IX. 


Degenerating  Leucocytes  in  Myelogenous  Leukemia. 
(Triacid  Stain.) 


Fig. 

I. 

Fig. 

2. 

Fig. 

3- 

Fig. 

4- 

Figs 

■  5 

Fig. 

7- 

Fig. 

8. 

Myelocyte  deficient  in  neutrophile  granules. 

Necrotic    myelocyte,    complete  karyolysis  ;  hydropic  degeneration  ;    loss  of   neutrophile 

granules. 
Degenerating  myelocyte.      Hydrops  of  nucleus. 

Polynuclear  leucocyte,  deficient  in  neutrophile  granules  ;  hydrops  of  nucleus. 
6.   Polynuclear  leucocytes.   Loss  of  neutrophile  granules.    Advanced  subdivision  of  nucleus. 
Myelocyte  in  mitotic  division.      (  Eosin  and  methylene  blue.) 
Eosinophile  leucocyte.     Some  granules  basophilic. 


I 


THE  LEUCOCYTES.  213 

(average  46  percent)  of  polynuclear  leucocytes.  Even  when  the  mye- 
locytes are  relatively  few  their  presence  seems  always  to  be  at  the  ex- 
pense of  polynuclear  cells,  a  fact  which  indicates  a  slower  progress  to 
full  development  as  well  as  increased  production  of  these  cells  in  the 
marrow.  The  most  successful  demonstration  of  nuclear  figures  in 
these  cells  {e.  g.,  by  Nocht's  stain)  shows  very  numerous  transitional 
forms  between  the  spheroidal  and  the  multilobate  nucleus,  while  after 
the  triacid  stain  it  is  usually  impossible  to  distinguish  between  many 
single  and  polymorphous  nuclei  in  neutrophile  cells. 

In  lymphatic  leukemia  polynuclear  leucocytes  are  usually  scarce  and 
may  not  be  found  at  all. 

Degenerative  changes  in  the  polynuclear  leucocytes  are  very 
common  and  very  marked.  Their  cohesiveness  is  increased  and  they 
appear  in  large  inseparable  groups  with  myelocytes.  Their  nuclei  are 
usually  pale  (karyolysis)  and  may  become  excessively  faint.  Gump- 
recht  suggests  that  this  pallor  of  the  nuclei  of  neutrophile  cells  indicates 
the  transformation  of  the  nucleins  into  xanthin  bodies.  Or,  the  lobes 
may  become  more  numerous,  entirely  separate,  very  compact  and  densely 
staining  (pyknomorphous),  while  the  granular  cytoplasm  is  replaced  by 
homogeneous  highly  refractive  material.  (Plate  IX.,  Figs.  5,  6.)  Or, 
the  nuclei  may  undergo  hydropic  degeneration.  (Plate  IX.,  Fig.  4.) 
All  grades  of  deficiency  of  granules  may  be  observed,  but  the  writer 
has  been  unable  to  demonstrate  fat  or  glycogen  in  the  neutrophile  cells 
of  leukemia.  Considerable  variations  in  the  size  of  these  cells  may 
be  noted  in  some  cases  of  leukemia. 

3.  Eosinophile  cells  are  usually  much  increased  in  number  in  myelo- 
cythemia  but  their  proportions  to  other  forms  of  leucocytes  commonly 
vary  within  normal  limits.  In  some  cases,  however,  the  proportions 
are  increased  but  never  so  much  as  in  cases  of  pemphigus,  etc.  Their 
proportions  are  not  pathognomonic  of  the  disease,  but  in  most  cases  their 
total  numbers  greatly  exceed  those  found  in  any  other  conditions.  Ehrlich 
places  their  numbers  between  3,000-100,000  per  cmm.,  thereby  prac- 
tically demonstrating,  as  he  originally  claimed,  that  the  excess  of 
eosins  is  among  the  pathognomonic  signs  of  the  disease.  In  some  spec- 
imens of  blood  the  eosinophile  cells  vary  greatly  in  size,  some  of  them 
being  very  small  while  their  neighbors  are  hypertrophic.  A  few  large 
basophilic  granules  may  be  found  in  the  polynuclear  as  in  the  mono- 
nuclear eosins  of  leukemia.     These  cells  are  actively  ameboid. 

In  acute  leukemia  of  both  types  and  in  chronic  lymphocythemia 
eosins  are  scarce  or  absent. 

Eosinophile  myelocytes  are  mononuclear  cells  with  eosinophile 
granules. 

In  some  of  these  cells  the  granules  are  of  uniform  size  and  staining 
quality,  or  there  may  be  some  basophile  granules  among  the  eosino- 
phile, or  the  granules  may  vary  greatly  in  size  and  in  density  of  stain. 
Eosinophile  myelocytes  7vith  granules  of  very  unequal  size  and  density  of 
stain  are,  in  the  writer's  experience,  pathognomonic  of  myelocythemia. 
(Plate  VII.,  Fig.  6.)     Bignami,  however,  speaks  of  the  occurrence 


214  LEUKEMIA. 

iu  pernicious  malaria  of  eosinophile   myelocytes  "  such  as  are  seen  in 
leukemia."  • 

In  the  majority  of  cases  of  myelocythemia  eosinophile  myelocytes 
constitute  a  large  proportion  of  all  eosinophile  cells  present.  In  lym- 
phatic leukemia  they  are  almost  always  absent,  and  in  acute  leukemia 
they  are  scarce  or  absent. 

4.  Lymphocytes. — The  numbers  and  proportions  of  lymphocytes  in 
myelocythemia  vary  in  different  cases  and  at  different  periods  in  the 
same  case.  It  may  still  be  stated  as  a  rule  that  the  more  purely  mye- 
logenous the  disease  the  smaller  is  the  proportion  of  lymphocytes.  But 
Muller  has  shown  that  the  exact  character  of  the  leukemic  process  in 
the  viscera  is  not  always  indicated  by  the  changes  in  the  blood,  and 
that  the  greatest  intensity  of  the  process  may  be  transferred  from  one 
organ  to  another.  One  must  therefore  be  prepared  to  find  marked 
variations  in  the  proportions  of  lymphocytes  without  being  able  always 
to  attach  much  significance  to  such  changes.  In  most  cases  the  lym- 
phocytes are  notably  diminished  in  proportion  while  probably  always 
increased  in  actual  numbers.  Cabot  found  an  average  of  10.6  percent, 
but  when  at  tiieir  lowest  (2  percent)  they  were  still  more  numerous 
than  in  normal  blood. 

5.  Large  mononuclear  leucocytes  with  very  faint  cytoreticulum  and 
vesicular  nucleus  are  seen  in  considerable  numbers  in  most  cases  of 
leukemia,  but  they  appear  to  lack  special  significance.  They  are  very 
apt  to  suffer  damage  in  the  smearing  process  and  to  appear  in  the  dry 
specimen  as  large  coarsely  reticular  nuclei  without  demonstrable  cell 
body.  (Plate  VIII.,  Fig.  3.)  These  cells  may  contain  granules  giving 
the  reaction  of  glycogen.  The  larger  forms  may  show  horseshoe-shaped 
nuclei.  In  the  cases  of  acute  leukemia,  described  by  Frankel  and 
others,  the  majority  of  cells  were  large  mononuclear  leucocytes. 

Degenerative  changes  are  noted  in  the  small  and  often  in  the 
large  lymphocytes  of  leukemia.  The  nuclei  of  the  small  cells,  instead 
of  remaining  compact,  may  become  incurved  and  finally  bilobed  or  tri- 
lobed,  while  the  cell  body  remains  basophilic.  (Rieder,  Ehrlich.) 
Litten  describes,"  in  two  acute  cases,  very  large  cells  in  which  the 
nucleus  was  obscured  by  many  globules  of  fat  blackened  by  osmic  acid. 
There  are  some  other  reports  of  fatty  degeneration  of  leucocytes  in 
leukemia,  but  apparently  none  from  very  recent  literature.  Mitotic 
figures  in  lymphocytes  of  lymphemia  are  reported  by  Wertheim. 

6.  Mast-cells. — These  cells  are  very  constantly  increased  in  chronic 
myelogenous  leukemia,  but  in  some  cases  a  prolonged  search  is  required 
for  their  discovery.  Although  occasionally  seen  in  other  conditions,  in 
leukemia  they  are  usually  so  markedly  increased  as  to  constitute  a  very 
reliable  diagnostic  feature  of  the  blood.  Thev  are  at  times  more 
abundant  than  the  eosins.  They  are  usually  absent  in  lymphemia  and 
the  writer  has  failed  to  find  them  in  acute  myelocythemia. 

Strauss  found  5  percent  of  mast-cells  among  the  leucocytes  in  blister- 
fluid  from  a  case  of  myelogenous  leukemia,  and  Milchner  reports  23.9 
percent  of  mast-cells  in  the  sediment  from  ascitic  fluid  in  a  similar  case. 


PLATE    VIII. 


"^S^" 


.   */ 


Lymphatic  Leukemia.     (Eosin  and  Metliylene   Blue. 


Figs.  I.  Small  lymphocytes. 

Figs.  2.     Medium-sized  and  large  lymphocytes. 

Fig.  3.  Degenerating  basket-shaped  nucleus  of  large  lymphocyte,  without  cytoplasm. 

Fig.  4.  Polynuclear  leucocyte.      Nodal  points  of  cytoreticulum. 

Fig.  5.  Red  cell.      Polychroraasia  of  Maragliano. 


SPECIAL   CHARACTERS  IN  LYMPHEMIA.  215 

Special  Characters  of  the  Blood  of  Lymphatic  Leukemia. — In 

this  type  of  the  disease  the  lymphocytes  are  the  only  form  of  white 
cell  appearing  in  the  blood  in  increased  numbers.  In  cases  in  which 
a  positive  clinical  diagnosis  is  possible  the  nature  of  the  condition  is  at 
once  evident  from  the  great  abundance  of  these  cells,  but  owing  to  the 
numerous  other  causes  of  chronic  lymphocytosis,  it  is  at  present  impos- 
sible to  state  what  is  the  lowest  proportion  of  such  cells  seen  in  the 
blood  of  genuine  cases.  In  well-marked  cases  they  are  quite  as  numer- 
ous as  the  leucocytes  of  myelocythemia,  while  some  of  the  highest  counts 
on  record  have  been  reported  in  cases  of  this  type. 

Usually  the  lymphocytes  are  of  small  size  and  normal  structure  and 
the  writer  has  specimens  of  one  very  marked  case  in  which  almost  all 
the  leucocytes  are  small  mononuclears.  Their  percentage  commonly 
runs  between  80-90. 

In  rather  rare  cases  reported  by  Frankel,  Grawitz,  Cabot,  and 
others,  and  in  one  child  observed  by  the  writer,  the  great  majority  of 
the  cells  were  unusually  large  and  their  cytoreticulum  faintly  staining. 
Between  the  two  extremes  are  cases  showing  various  proportions  of 
small,  medium-sized,  and  large  lymphocytes.  The  small  lymphocytes 
are  usually  more  abundant  in  chronic  cases  and  in  adults,  the  larger 
cells  tending  to  become  prominent  in  acute  cases  and  in  children. 
Gerhardt  refers  to  a  case  in  which  large  lymphocytes,  abundant  in  the 
early  acute  stage,  were  replaced  during  a  chronic  course  of  six  months 
by  small  lymphocytes. 

Frankel  believed  that  these  cells  could  be  regarded  as  pathognomonic 
of  acute  lymphatic  leukemia,  but  his  claims  have  been  fully  disproved. 
(Grawitz.)  Large  mononuclear  cells  with  hyaline  bodies  were  common  iu 
the  writer's  cases  of  acute  myelocythemia,  and  reasons  have  been  given  to 
show  that  some  of  these  cells  may  result  from  loss  of  neutrophile  granules 
of  myelocytes.  Hirschlaff  has  recently  reported  2  acute  cases  in  Avhich  most 
of  the  leucocytes  were  large  mononuclear  cells  without  granules.  In  a 
moderate  proportion  of  them  neutrophile  granules  and  in  a  larger  number, 
eosinophile  granules  were  noted. 

This  variation  in  size  of  lymphocytes  may  have  an  anatomical  basis  in  the 
structure  of  the  hyperplastic  lymph  nodes,  as  in  some  cases  these  nodes  con- 
tain mostly  small  lymphocytes  ;  at  other  times  large  mononuclear  cells. 
(Birch-Hirschfeld,  Benda.) 

These  and  other  considerations  oppose  the  interesting  view  recently  ex- 
pressed by  Rosenfeld,  that  when  the  lesion  of  lymphemia  is  in  the  marrow 
many  large  lymphocytes  appear  in  the  blood,  anemia  rapidly  develops,  and 
the  disease  runs  a  severe  course,  while  if  the  lesion  affects  only  spleen  and 
lymph  nodes  large  lymphocytes  are  absent  from  the  blood  and  anemia  is  of 
slow  development. 

Myelocytes,  both  neutrophile  and  eosinophile,  and  mast-cells,  are 
usually  absent  or  extremely  scarce  in  lymphemia,  but  are  occasionally 
seen  in  scant  numbers.  (MuUer.)  Polynuclear  leucocytes,  both  neu- 
trophile and  eosinophile,  are  also  comparatively  scarce. 

The  red  cells  suffer  the  same  changes  as  are  seen  in  myelocythemia, 
but  nucleated  red  cells  are  usually  very  scanty  and  may  not  be  found 
at  all. 


216  LEUKEMIA. 

Variations  in  the  Blood  Changes  in  Leukemia. — Both  the  num- 
bers and  the  proportions  of  leucocytes  in  leukemia  are  subject  to  con- 
siderable variations  from  many  causes. 

1.  Intercurrent  Diseases. — A  considerable  number  of  cases  have 
been  reported  showing  that  intercurrent  infections  may  greatly  alter 
the  appearance  of  the  blood  in  leukemia.  These  cases  have  been  col- 
lected by  Frankel  and  Marischler,  Froelich,  Cabot,  Kormoczi,  and 
McCrae.  Some  of  the  reports  refer  to  terminal  septicemia  which  has 
resulted  usually  in  a  marked  and  rapid  decrease  of  leucocytes,  without 
great  change  in  the  proportions  of  the  different  forms.  Frankel,  who 
saw  the  leucocytes  fall  from  220,000  to  1,200,  refers  this  result  to  pure 
leucocytolysis.  Such  cases  have  been  observed  after  typhoid  fever, 
pneumonia,  empyema,  erysipelas,  septicemia,  tuberculosis,  carcinoma, 
etc.,  but  distinct  changes  in  leukemic  blood  do  not  invariably  result 
from  such  intercurrent  diseases.  In  cases  where  the  infection  is  local- 
ized (empyema,  erysipelas)  the  normal  activities  of  the  marrow  seem  to 
be  stimulated,  and  while  the  leucocytes  diminish  the  proportion  of 
polynuclear  cells  increases.  (Freudenstein,  Kovacs,  Muller.')  Kraus 
has  recently  reported  a  reduction  of  from  393,000  to  4,000  leucocytes  in 
a  few  days  as  the  result  of  double  pneumonia  and  empyema.  The  vis- 
cera (marrow,  liver,  spleen)  showed  no  evidence  of  leukemic  infiltra- 
tion, and  Kraus  suggests  that  the  suppurative  process  had  not  only 
transformed  the  blood,  but  had  resolved  the  essential  visceral  lesions 
as  well.  Usually,  intercurrent  infections  diminish  the  volume  of 
spleen  and  lymph  nodes  even  when,  as  in  MuUer's  case,  the  leucocytes 
are  increased.  After  the  subsidence  of  the  infection  the  blood  soon 
resumes  its  original  condition  (Grawitz),  or  even  before  the  infection 
subsides,  the  first  effect  may  pass  off,  as  occurred  in  Eisenlohr's  case 
within  fourteen  days. 

Although  no  permanent  improvement  resulted  iu  any  cases  siiffering  from 
intercurrent  infections,  several  attempts  have  been  made  to  favorably  influ- 
ence the  course  of  leukemia  hy  artificial  leucocytosis.  Jacob  reduced  the 
leucocytes  from  850,000  to  282,000  in  a  few  days  by  repeated  injections  of 
glycerine  extract  of  spleen,  but  could  not  report  any  improvement  in  the 
patient.  The  same  result  was  obtained  by  Richter  using  spermin.  Richter 
and  Spiro  claim  to  have  increased  the  leucocytes  in  leukemia  from  170,000 
to  560,000  within  3  hours  after  injection  of  cinnamic  acid,  followed  by 
prompt  return  to  the  previous  condition.  Heuck2  has  also  reduced  the 
leucocytosis  of  leukemia  by  injection  of  tuberculin.  In  mild  inflammatory 
processes  there  may  be  no  effect  upon  the  leucocytes  of  leukemia,  as  indi- 
cated by  the  cases  of  Richter  and  Heuck.i 

Ante-mortem  leucocytosis  of  considerable  degree  (172,000)  was  ob- 
served by  Thorsch  in  a  case  complicated  by  pneumonia.  In  a  case  of 
lymphatic  leukemia  dying  of  septicemia  Muller  found,  four  days  before 
death,  400,000  leucocytes  when  there  had  previously  been  but  180,000. 
A  differential  count  was  not  made,  but  Muller  regarded  the  increase  as 
referable  to  a  polynuclear  leucocytosis. 

Chronic  infections  have  much  less  effect  in  altering  the  character  of 
leukemic  blood.     Quincke,  and  Stintzing,  reported  a  general  improve- 


I 


CHEMISTRY.  217 

ment  of  the  leukemic  process  during  acute  miliary  tuberculosis  and 
during  an  exacerbation  of  chronic  phthisis. 

In  a  case  of  lymphatic  leukemia  dying  with  carcinoma  of  the  kidney, 
Marischler  found  a  decrease  of  leucocytes  from  96,000  to  48,000,  with 
marked  increase  in  the  proportion  of  polynuclear  cells. 

2.  Spontaneous  Changes  in  the  Blood  of  Leukemia. — A  few 
instances  are  recorded  in  which  the  disease,  as  indicated  by  the  blood 
changes,  was  slowly  transformed  from  one  type  into  another.  The  first 
of  these  cases  was  that  of  Fleischer  and  Penzoldt  who  observed  splenic 
leukemia  pass  into  lymphatic.  It  seems  possible  that  this  case  may  be 
placed  with  others  described  by  FrankeP  and  Gerhardt,  in  which  lym- 
phatic leukemia  began  acutely  with  large  lymphocytes  but  progressed 
more  slowly  with  small  lymphocytes.  Wey  observed  a  case  of  mye- 
locythemia  in  which,  within  ten  weeks,  the  polynuclear  cells  fell  from 
33.5  percent  to  3.7  percent,  the  mononuclears  rose  from  66.5  to  96.3 
percent  among  which  were  neutrophile  myelocytes,  large  hyaline  cells, 
and  a  few  lymphocytes. 

Gerhardt  observed  the  blood  of  a  case  of  leukemia  of  marked  grade 
pass  into  that  of  pernicious  anemia,  the  excess  of  leucocytes  disappear- 
ing in  three  days.  The  possible  transformation  of  pernicious  anemia 
into  leukemia  has  already  been  discussed. 

Pseudo-leukemia  has  been  shown  to  change  into  leukemia  in  several 
authentic  cases.     (See  Pseudo-leukemia.) 

Chemistry.  Specific  Gravity. — The  specific  gravity  of  the  blood 
is  usually  reduced  owing  principally  to  the  loss  of  Hb.  But  leukemia 
is  one  condition  in  which  Hb  is  often  replaced  by  other  albumens,  so 
that  the  gravity  of  the  blood  is  relatively  high  in  comparison  to  the 
Hb-content,  and  in  exact  proportion  to  the  increase  of  leucocytes. 
Thus  Dieballa  reports  a  case  with  2.6  million  red  cells,  750,000  leu- 
cocytes, and  gravity  of  1.060.  The  lowest  observations  are  placed  by 
Grawitz  between  1.029-1.023.  The  low  figures  are  usually  seen  in 
cases  complicated  by  hemorrhages  or  other  causes  of  secondary  anemia. 

Alkalescence. — The  alkalescence  of  leukemic  blood  has  been 
found  by  v.  Jaksch,  Peiper,  and  others,  to  be  much  diminished.  Early 
observers  found  the  blood  distinctly  acid  soon  after  death  (Scherer), 
probably  owing  to  the  post-mortem  formation  of  acids,  v.  Noorden  re- 
ferred the  diminished  alkalinity  to  the  development  of  acids  during  life. 
Lactic  and  formic  acids  have  been  isolated  from  the  fresh  blood  by 
Scherer,  Hosier,  et  ciL,  and  acetic  acid,  after  death  only,  by  Hosier. 

Albumens. — Fibrin  has  been  found  in  excessive  quantity,  5.7  per- 
cent (normal  .25  percent),  by  Parkes,  but  in  chronic  cases  with  severe 
anemia  it  is  diminished.      (Robin.) 

Peptone. — Considerable  interest  attaches  to  the  demonstration,  first 
by  Bockendahl  and  Landwehr,  of  considerable  traces  of  peptone  in  the 
splenic  pulp  and  in  the  blood  of  leukemia.  This  observation  has  lately 
been  verified  by  Hathes,  who,  however,  has  shown  that  the  principle 
in  question  is  not  Kuhne's  peptone,  but  deutero-albumose.  Freund 
believes  that  the  retarded  coagulation  of  leukemic  blood  is  largely  ref- 


218  LEUKEMIA. 

erable  to  the  presence  of  albumose.  The  products  of  the  excessive 
destruction  of  leucocytes  have  been  traced  in  the  presence  of  their  vari- 
ous derivatives  in  blood  and  urine. 

NucLEO-ALBUMEX  has  been  isolated  from  the  serum  by  Mathes ; 
mucin  or  a  closely-allied  substance  by  Scherer  and  others  ;  and  a  prin- 
ciple resembling  gluten  by  Salkowski. 

Xanthin  bodies,  which  represent  further  decomposition-products 
of  leucocytes,  have  been  found  in  the  spleen  and  blood  by  Scherer  and 
many  others.  The  xanthin  bodies  of  Kossel  are  more  abundant  and 
more  easily  recognized  in  leukemic  than  in  normal  blood. 

Uric  acid  has  been  found  in  traces  by  Hosier,  Fowlwarczny,  Klem- 
perer,  and  Weintraud.  An  excessive  excretion  of  uric  acid  in  the 
urine  of  leukemia  has  often  been  observed,  and  Magnus-Levy  reported 
as  high  as  8  gr.  daily,  but  since  the  most  abundant  appearance  of  leu- 
cocytes need  not  indicate  the  time  of  their  greatest  destruction,  there 
is  no  parallel  between  the  excretion  of  this  principle  and  the  excess  of 
white  cells  in  leukemia.     (Minkowski.) 

An  increased  quantity  of  glycogen  has  been  extracted  by  Salomon 
and  by  Gabritschewsky.  The  fat-extract  has  been  found  distinctly  in- 
creased by  Robertson,  Isambert  (.72  percent),  and  Freund  and  Ober- 
mayer. 

Tyrosin  was  isolated  by  Fowlwarczny,  and  lecithin  and  choles- 
TERIN  from  the  blood  of  a  hematoma  by  Freund  and  Obermayer. 

Of  Inorganic  principles  the  iron  has  uniformly  been  found  di- 
minished (2.24-2.97  percent  of  ash)  usually  in  proportion  to  the  loss 
of  Hb.     (Strecker,  Scherer,  Freund  and  Obermayer.) 

Phosphorus  and  sulphur,  and  sodium  were  much  increased  and  potas- 
sium and  chlorine  much  diminished  in  Freund  and  Obermayer's  ^  case, 
while  the  total  salts  were  moderately  increased. 

Charcot-Leyden  Crystals. — Robin  first  observed  these  peculiar  crys- 
tals in  the  tissues  of  a  leukemic  cadaver,  and  they  were  described  by 
Charcot  and  Robin  in  1853.  Zenker  later  (1855)  claimed  priority  in 
their  discovery.  They  were  found  in  all  parts  of  the  circulation  in  a 
case  examined  after  death  by  Wallace  in  1855.  Later  they  were  care- 
fully studied  by  Charcot  and  Vulpian,  who  described  them  as  color- 
less, refractive,  elongated  octahedra,  .016  x  .005  mm.,  or  occasionally 
of  much  larger  dimensions,  insoluble  in  cold  water,  alcohol,  ether,  or 
glycerine,  soluble  in  hot  water  and  in  most  acids  and  alkalis.  After 
death  they  appear  in  the  blood,  exudates,  and  especially  in  the  spleen, 
and  their  numbers  increase  with  post-mortem  changes  in  the  tissues. 
Like  most  other  crystals  of  post-mortem  formation  they  are  often  seen 
in  or  on  the  leucocytes.  Their  occurrence  in  sputum  and  relation  to 
eosinophile  cells  was  pointed  out  by  Charcot  and  Leyden.  According 
to  Neumann  ^  they  are  found  in  leukemia  only  when  the  blood  con- 
tains many  large  cells  with  abundant  cytoplasm  and  large  nuclei,  and 
hence  are  not  seen  in  lymphatic  leukemia.  Chemically  they  were  re- 
garded by  Charcot  as  albuminates,  by  Salkowski  as  mucinous.  Lately, 
Pohl  has  shown  that  they  are  identical  with  Bottcher's  spermin  crystals. 


THE  DIAGNOSIS  OF  LEUKEMIA.  219 

which  are  a  product  of  the  destruction  of  the  nucleins  of  disintegrating 
cells,  and  probably  consist  of  spermin  phosphate.  Scherer  also  con- 
cluded that  they  are  composed  of  phosphoric  acid  and  an  organic  base. 

They  were  obtained  in  the  blood  drawn  during  life  by  Neumann 
and  later  by  many  others. 

They  are  not  peculiar  to  leukemia,  but  appear  in  the  sputum  of 
asthma,  in  feces  and  mucus  surrounding  intestinal  parasites,  and  have 
been  found  in  the  fetal  blood  in  simple  anemia.     (Gowers.) 

The  Diagnosis  of  Leukemia. — In  no  other  department  is  the  ex- 
amination of  the  blood  to  be  interpreted  with  greater  certainty  in  one 
case  or  greater  reserve  in  another,  than  in  its  application  to  the  va- 
rious types  of  leukemia. 

1.  TJie  changes  in  the  blood  may  yield  positive  diagnostic  signs  of 
leukemia. 

This  result  is  obtained  in  the  great  majority  of  cases  of  both  types, 
whether  acute  or  chronic. 

These  signs  are  briefly  : 

In  myelocythemia. — An  excessive  leucocytosis  (150,000-1,000,000). 

A  large  number  and  considerable  proportion  of  neutrophile  myelo- 
cytes (20-60  percent). 

A  large  number  of  eosinophile  cells  (3,000-100,000)  of  which  many 
are  mononuclear  and  exhibit  very  large  densely  staining  granules. 

An  excessive  number  of  polynuclear  neutrophile  cells.  Character- 
istic changes  in  the  red  cells. 

To  these  may  be  added  :  The  presence  of  many  mast-cells,  many 
nucleated  red  cells,  mitotic  nuclei  in  leucocytes,  extreme  and  peculiar 
degenerative  changes  in  leucocytes. 

In  chronic  lyinphocythemia. — An  excessive  leucocytosis  (150,000- 
1,000,000). 

The  presence  of  85-99  percent  of  lymphocytes. 

Scanty  numbers  of  myelocytes,  eosins,  nucleated  red  cells,  and 
mast-cells. 

For  the  positive  diagnosis  of  either  type  of  the  disease  the  essential 
point  is  the  excessive  leucocytosis,  at  least  150,000  cells,  of  which  a 
considerable  proportion  are  myelocytes  or  a  still  higher  proportion  are 
lymphocytes. 

No  other  condition  thus  far  observed  yields  such  characters  in  the 
blood,  in  the  presence  of  which  the  diagnosis  of  leukemia  is  established 
beyond  doubt. 

2.  The  changes  in  the  blood  may  justify  only  a  probable  diagnosis 
of  leukemia.     This  situation  is  encountered  under  several  conditions. 

(rt)  In  myelocythemia,  the  eifect  of  intercurrent  infections  may  so 
reduce  the  number  of  leucocytes  and  especially  the  proportion  of  my- 
elocytes that  the  blood  does  not  differ  from  that  of  some  cases  of  acute 
inflammatory  leucocytosis  with  5-16  percent  of  myelocytes.  (Diph- 
theria (Engel),  pneumonia  (Turk).) 

(6)  In  the  less  marked  stages  of  lymphocythemia,  especially  of  the 
acute  form,  the  number  and  proportion  of  lymphocytes  may  be  far  from 


220  LEUKEMIA. 

characteristic  of  leukemia.  When  there  are  less  than  150,000  white 
cells  and  less  than  90  percent  of  lymphocytes,  the  condition  of  the 
blood  does  not  differ  from  that  seen  in  some  forms  of  inflammatory 
leucocytosis,  or  of  lymphocytosis  in  the  secondary  anemia  of  children, 
or  of  the  obscure  condition  called  "  v.  Jaksch's  anemia."  In  inflam- 
matory lymphocytosis,  however,  there  are  always  a  fair  proportion  of 
polynuclear  leucocytes,  which  are  very  scanty  in  lymphemia,  and  the 
lymphocytosis  is  usually  transient. 

In  secondary  anemia  the  lymphocytosis  is  seldom  excessive,  the  pro- 
portion of  lymphocytes  is  usually  lower,  and  a  few  myelocytes,  eosins, 
and  nucleated  red  cells  are  commonly  present. 

In  "  V.  Jaksch's  anemia  "  the  lymphocytes  are  usually  less  numer- 
ous, there  are  more  large  hyaline  mononuclear  leucocytes  than  are 
usually  seen  in  lymphemia  of  equal  chronicity,  and  myelocytes,  eosins, 
and  many  nucleated  red  cells,  are  usually  present. 

Frankel  has  classed  as  acute  lymphemia  certain  obscure  cases  attended 
with  moderate  hyperplasia  of  lymph  nodes  and  the  presence  in  the  blood  of 
a  considerable  number  of  cells  regarded  by  some  as  large  lymphocytes. 
Frankel's  cases  have  not  been  fully  accepted  by  his  countrymen,  and 
Grawitz  especially  has  shown  that  the  above  condition  of  the  blood  is  not 
pathognomonic  of  lymphemia,  while  Benda  has  paved  the  way  for  the  divi- 
sion of  these  cases  into  other  categories,  including  acute  myelocythemia. 
Frankel's  cases  may  belong  in  the  class  of  lymphocythemia,  but  the  condi- 
tion of  the  blood  is  not  characteristic  and  the  result  of  his  autopsies  is  in- 
conclusive. 

3.  In  some  stages  of  leukemia  the  blood  may  fail  to  furnish  indica- 
tions of  the  nature  of  the  disease,  which  may  then  be  overlooked. 

(a)  Intercurrent  infections  have  been  shown  to  temporarily  trans- 
orm  the  blood  of  leukemia  into  that  of  inflammatory  leucocytosis. 

(6)  In  a  case  of  acute  myelocythemia,  with  the  disease  fully  estab- 
lished, the  writer  found  on  first  examination  5  percent  of  myelocytes 
with  a  leucocytosis  of  ordinary  inflammatory  grade.  Later  the  myelo- 
cytes increased  to  the  lower  limits  of  leukemia,  but  a  positive  diagnosis 
was  not  established  until  the   marrow  was  examined  microscopically. 

(e)  Most  writers  agree  that  the  early  stages  of  leukemia  often  escape 
detection,  and  that  many  spurious  cases  have  appeared  in  literature. 

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Gabritschewsky.     Archiv  f.  exper.  Path.,  Bd.  28,  p.  272. 

Gerhardt.     XV.  Cong.  inn.  Med.,  p.  382. 

Gilbert.     Path,  du  Sang.  Traite  de  Med.  (Charcot),  Paris,  1892,  IT.,  p.  457. 

Gowers.     Reynold's  Syst.  Med.,  1879,  V.,  p.  216. 

Grawitz.     Klin.  Path,  des  Blutes. 

Green.     N.  Y.  Med.  Jour.,  1888,  Feb. 

Greiwe.     Berl.  klin.  Woch.,  1892,  No.  33. 

Giimprecht.     Deut.  Archiv  klin.  Med.,  Bd.  57,  p.  523. 

Guttmann.     Berl.  klin.  Woch.,  1891,  p.  1109. 

Hajek.     Wien.  klin.  Woch.,  1897,  No.  20. 

Hayem.     Du  Sang.,  pp.  382,  856,  857. 

Herzjeld.     N.  Y.  Polyclinic,  1894. 

Heuck.     'Virchow's  Archir,  Bd.  78,  p.  475.     ^T>e\xt.  med.  Woch.,  1891,  p.  747. 

Hinierberger.     Deut.  Archiv  klin.  Med.,  Bd.  48,  p.  324. 

Hirschlaff.     Deut.  Archiv  klin.  Med.,  Bd.  62,  p.  314. 

Isambert.     Cited  by  Mosler. 

Jacob.     Cited  by  Grawitz,  p.  127. 

Jaderhohn.     Cited  by  Litten  (Nothnagel,  Spec.  Path.),  p.  148. 

V.  Jaksch.     Zeit.  f.  klin.  Med.,  Bd.  23,  p.  187,  also  Klin.  Diagnostik. 

Kelsch,   Vaillard.     Annal.  de  I'Institut  Pasteur,  1890. 

Klebs.  'Virchow's  Archiv,  1867,  Bd.  38,  p.  190.  ^Eulenberg's  Realencyc,  Bd. 
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Klein.     Cited  by  Pawlowsky. 

Klemperer,  Weintraud.     Deut.  med.  Woch.,  1895,  No.  40,  V.  B. 

Kormoczi.     Deut.  med.  Woch.,  1899,  p.  775. 

Kottman.     Inaug.  Diss.  Bern.,  1871. 

Kottnitz.     Berl.  klin.  Woch.,  1890,  No.  35. 

Kovacs.     Wien.  klin.  Woch.,  1893,  p.  701. 

Kraus.     Prag.  med.  Woch.,  1899,  No.  41. 

Lenbe,  Fleischner.     Virchow's  Archiv,  Bd.  83,  p.  124. 

Limbeck.     Prag.  med.  Woch.,  1893,  Nos.  12-14. 

Litten.  'Berl.  klin.  Woch.,  1877,  p.  256,  also  Krankh.  d.  Milz.  ( Nothnagel' s  spec. 
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p.  22.    2  Die  Leukemic  als  Protozoeninfec.  Also,  XVIII.  Cong.  inn.  Med.,  pp.  251,  322. 

Magnus,  Levy.     Cited  by  Litten. 


222  LEUKEMIA. 

Mannaberg.     XIV.  Cong.  f.  inn.  Med.,  p.  252. 

Marischkr.     Wien.  klin.  Woch.,  1896,  p.  686. 

Masius,  Fmncotte.     Cited  by  Ebstein. 

Mathes.     Berl.  klin.  Woch.,  1894,  pp.  531,  556. 

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McCrae.     Brit.  Med.  Journ.,  1900,  I.,  p.  760. 

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Milchner.     Zeit.  f.  klin.  Med.,  Bd.  37,  p.  194. 

Minkowsky.     XVII.  Cong.  f.  inn.  Med.,  1899. 

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Mosler,  Westphal.     Semaine  Med.,  1889,  p.  372. 

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1878,  p.  607. 

V.  Noorden.     Path,  des  Stoffwechsels,  1893,  p.  342. 

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Parkes.     Med.  Times,  1851. 

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Ffeiffer.     Cited  by  Litten  (Nothnagel's  Path. ). 

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Ponfiek.     Virchow's  Archiv,  Bd.  ()7,  p.  368. 

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Sehede,  Stahl.  Mittheil.  a.  d.  Chir.  Abt.,  Friedrichshain  Hosp.  Berlin,  Leipsic, 
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Zenker.     Deut.  Archiv  klin.  Med.,  1876,  p.  125. 


CHAPTER    IX. 
PSEUDO-LEUKEMIA. 

Definition. — Pseudo-leukemia  is  a  primary  disease  of  the  lymphatic 
structures,  characterized  by  progressive  enlargement  of  various  chains 
of  lymph  nodes  and  of  the  spleen,  by  metastatic  growths  of  lymphoid 
tissue  in  many  localities,  and  by  progressive  anemia,  but  diifering  from 
leukemia  chiefly  in  the  absence  of  marked  leucocytosis. 

The  disease  does  not  belong  with  aifections  of  the  blood,  but  on  ac- 
count of  its  pathological  resemblance  to  leukemia,  is  properly  described 
in  this  connection. 

Historical. — The  first  attempt  to  demonstrate  the  specific  character 
of  the  lymphadenopathy  of  the  disease  appeared  in  1828  when  Craigie 
called  attention  to  the  dilEference  between  certain  firm  tumors  of  lymph 
nodes  and  the  caseating  scrofulous  and  the  cancerous  enlargements. 
In  1832  Hodgkin  described  several  cases  observed  chiefly  at  Guy's 
Hospital,  some  of  which  were  cancerous,  tuberculous,  or  syphilitic, 
but  two  of  which  were  undoubtedly  genuine  examples  of  pseudo-leu- 
kemia. He  distinguished  the  "■  organized  "  nodes  from  the  caseous 
and  cancerous  ones. 

Before  the  discovery  of  leukemia  therefore  it  was  known  that  there 
are  enlargements  of  the  lymph  nodes  apart  from  cancer  and  tuberculo- 
sis. In  1839  Velpeau  drew  attention  to  the  occurrence  of  hypertro- 
phied  lymph  nodes  apart  from  scrofula.  In  1856  Wilkes  described 
several  cases  which  he  regarded  as  a  special  form  of  disease  of  lymph 
nodes  but  did  not  fully  distinguish  the  lesions  from  those  of  tuberculosis. 

The  first  complete  description  of  the  malady  appears  to  have  been 
that  of  Wunderlich,  1858,  who  noted  an  idiopathic  origin  of  the  dis- 
ease, and  the  cellular  character  of  the  new  growths  in  both  nodes  and 
spleen,  mentioned  the  severe  anemia,  and  called  attention  to  the  ab- 
sence of  the  extreme  leucocytosis  which  characterizes  leukemia.  In 
the  same  year,  1858,  Billroth  described  the  histological  structure  of 
the  enlarged  nodes,  noting  the  limitation  within  the  capsule,  the  oblit- 
eration of  follicles  and  of  lymph  sinuses  and  vessels,  the  proliferation 
of  cells  by  nuclear  division,  and  concluding  that  the  hyperplasia  is 
closely  related  to  and  may  pass  into  sarcomatosis.  Recognizing  in  the 
condition  a  tumor  of  lymph  nodes  of  fatal  tendencies  but  differing 
from  sarcoma,  he  employed  the  term  "  malignant  lymphoma  "  as  spe- 
cially applicable  to  this  condition.  In  1864  the  general  pathological 
features  were  described  by  Virchow  under  the  term  "  lymphosarcoma." 
Cohnheim  in  1867  described  a  case,  and  noting  especially  the  absence 
of  leucocytosis  suggested  the  term  "pseudo-leukemia." 

The  nearly  constant  afi'ection  of  the  spleen  was  noted  by  the  earlier 


224  PSEUDO-LEUKEMIA. 

observers,  AVilks,  Woillez,  Griesinger,  Muller,  and  Strumpel,  and  the 
prominence  of  this  symptom  in  some  cases  led  Griesinger  to  employ 
the  term  "  splenic  anemia  "  for  such  forms  of  the  malady. 

In  France  Bonfils  described  a  case  in  1858,  using  the  designation 
'- cachexia  sans  leukemia'^  on  account  of  the  absence  of  leucocytosis. 

A  few  other  examples  of  the  disease  were  reported  before  1865  when 
Trousseau  described  in  detail  the  clinical  characters  and  proposed  the 
term  "  adenia."  French  writers  from  Trousseau  to  Gilbert  have 
regarded  the  condition  as  very  closely  related  to  or  identical  with  leu- 
kemia, employing  the  term  "  lyinphadenie  aleukemique.'' 

In  1870  a  full  description  of  the  disease,  clinical  and  pathological, 
with  historical  notes  to  date  was  published  by  Murchison  and  Sander- 
son. Cornil  and  Ranvier  in  1867  very  fully  described  the  histological 
structure  of  the  nodes,  regarding  the  process  as  a  true  lymphadenoma. 
In  1887  Ebstein^  described  an  acute  form  of  the  malady.  Later 
writers  have  described  similar  cases  possibly  including  among  them 
some  conditions  not  related  to  pseudo-leukemia.     (Banti,  Potain,  Bruhl.) 

The  peculiar  localization  of  the  lesions  to  different  structures  has 
been  illustrated  in  many  reported  cases.  Bonfils  and  Trousseau  showed 
that  the  spleen  need  not  participate  at  all  in  the  lesion.  A  special 
aflFection  of  the  tonsillar  ring  was  described  by  Demange,  and  of  the 
intestinal  mucosa  by  Gilly,  and  later  by  many  others.  A  testicular 
form  has  been  described  by  Monod  and  Terillon.  A  case  of  Reine- 
berg's  indicates  that  the  lesion  may  be  limited  to  the  marrow. 

Many  have  regarded  the  anemia  infantum  pseudo-leukemica  of  v. 
Jaksch  as  the  splenic  form  of  Hodgkin's  disease  occurring  in  an  infant. 
(Luzet,  Gilbert.) 

The  dermal  type  of  the  disease  has  been  described  by  many  writers, 
including  Biesiadecki,  Kaposi,  Hochsinger  and  Schiff,  and  Joseph,  but 
appears  to  have  been  first  described  in  France,  by  Gillot. 

Anatomical  Characters. — The  lesions  in  reported  cases  of  the 
disease  have  included  inflammatory  hyperplasia  of  lymph  nodes,  lym- 
phadenoma, and  various  forms  of  sarcoma  of  lymph  nodes. 

1.  Simple  inflammatory  hyperplasias  have  been  described  in  genuine 
cases  in  slightly  swollen  glands,  not  yet  reached  by  the  true  lymph- 
adenomatous  process.     (Gowers.) 

2.  Lymphadenoma  or  Lymphoma. — In  the  majority  of  cases  the  lesions 
encountered  in  the  nodes  are  those  of  lymphadenoma,  i.  e.,  the  auton- 
omous growth  of  lymphoid  tissue  with  small  lymphocytes  supported 
by  reticular  connective  tissue. 

In  the  typical  chronic  cases  one  lymph  node  in  a  chain  is  affected,  fol- 
lowed by  the  other  members  of  the  chain,  or  the  entire  chain  is  affected 
simultaneously.  The  disease  seldom  spreads  by  gradual  extensions  from 
one  chain  to  another,  but  suddenly  involves  a  new  chain  on  the  same  or 
opposite  sides  of  the  body.  Sarcoma  of  lymph  nodes  affects  the  intervening 
tissues  between  chains  of  nodes.  For  a  long  period  the  swollen  nodes  are 
retained  in  their  capsules,  but  late  in  progressive  cases  the  members  of  the 
chain  are  variously  fused  and  their  capsules  largely  obliterated.  This  fusion 
may  result  either  from  rupture  of  the  capsules  or  from  periadenitis. 


ANATOMICAL   CHARACTERS.  225 

Microscopical  examination  shows  the  new  tissue  to  be  composed  of 
lymphocytes  supported  by  reticular  tissue.  There  are  considerable 
variations  in  the  character  both  of  the  cells  and  the  reticular  tissue. 
The  cells  are  usually  lymphocytes  of  small  and  medium  size,  among 
which  are  a  few  polynuclear  leucocytes  and  occasionally  (Goldman, 
Kanter)  eosinophile  cells.  They  are  either  diffusely  distributed,  or 
the  normal  follicles  may  be  preserved  for  a  long  period.  In  the  early 
stages,  or  in  less  active  growths,  the  lymph  paths  are  preserved,  but 
later  are  obliterated.  The  reticular  tissue  is  frequently  less  abundant 
than  in  the  normal  node,  later  a  diffuse  fibrosis  occurs  and  the  propor- 
tion of  cells  diminishes.  The  varying  proportions  of  cells  and  tissue 
yield  soft  and  cellular  or  hard  and  fibrous  growths.  The  latter  is 
probably  a  later  stage  of  the  former  condition,  but  all  stages  are  com- 
monly seen  in  different  nodes  of  the  same  subject,  and  dense  nodes  are 
said  to  have  been  replaced  by  softer  ones,  (Gowers.)  There  is  little 
tendency  in  these  structures  toward  caseation,  or  suppuration,  or  hya- 
line changes  of  chronic  tuberculosis. 

The  lymph  nodes  of  pseudo-leukemia  may  not  differ  in  microscopical 
structure  from  those  of  lymphatic  leukemia  in  any  known  particular. 
In  myelogenous  leukemia  the  lymph  nodes  commonly  show  a  diffuse 
growth  of  larger  mononuclear  cells.  According  to  Birch-Hirschfeld  ' 
the  nodes  of  leukemia  can  be  injected  through  afferent  vessels  and  the 
fluid  will  pass  through  into  the  efferent  vessels,  while  in  pseudo-leukemia 
the  injection  is  imperfect  and  fluid  fails  to  pass  through.  Attempts  to 
demonstrate  lymph  vessels  about  pseudo-leukemic  nodes  have  often 
failed  (Billroth)  but  sometimes  they  are  found  distended  with  lymph. 
The  occlusion  of  lymph  paths  may  prevent  the  afflux  into  the  general 
circulation  of  cells  from  lymph  nodes,  but  it  still  remains  an  obscure 
fact  that  the  very  abundant  and  unusually  diffuse  lymphoid  deposits 
in  the  viscera  fail  to  cause  lymphocytosis. 

3.  Lymphosarcoma. — In  many  cases,  especially  of  more  acute  type, 
the  lymph  nodes  in  the  group  are  fused  together,  capsules  and  sur- 
rounding structures  are  infiltrated  and  destroyed,  different  chains  are 
united  by  a  continuous  growth,  and  the  process  has  all  the  gross  char- 
acters of  a  malignant  tumor.  Such  nodes  show  no  traces  of  sinuses  or 
follicles  but  are  composed  of  a  diffuse  growth  of  cells  usually  larger 
than  lymphocytes,  often  containing  giant-cells,  and  sometimes  masses 
of  fusiform  cells. 

Two  views  are  possible  regarding  the  classification  of  such  growths. 
One  may  enlarge  the  scope  of  the  term  pseudo-leukemia  to  include 
lymphosarcoma  or  may  throw  out  such  cases  of  lymphosarcoma  and 
limit  the  application  of  the  term  to  the  lymphadenomata.  In  the 
present  state  of  our  knowledge,  there  apjiears  to  be  no  escape  from  the 
former  alternative.  There  appear  to  be  all  transitional  forms  between 
the  chronic  lymphomata  and  the  rapidly  growing  infiltrating  giant- 
celled  lymphosarcomata.  In  at  least  one  case  it  has  been  possible  to 
observe  the  transformation  of  pseudo-leukemia  into  sarcoma  of  lymph 
nodes.  (Eisenmenger.)  Moreover,  of  the  cases  of  pseudo-leukemia 
15 


226  PSEUDO-LEUKEMIA. 

which  have  passed  into  leukemia  some  have  shown  the  histological 
structure  of  giant-celled  lymphosarcoma.  There  remains  as  a  separate 
class  of  sarcoma  of  lymph  nodes,  the  spindle-celled  sarcomata  or  endo- 
theliomata,  which  arise  from  the  reticular  stroma. 

Acute  Pseudo-leukemia. — Various  acute  and  fatal  processes  of 
somewhat  uncertain  nature  have  been  classed  with  pseudo-leukemia. 

1.  That  true  pseudo-leukemia  may  run  an  acute  course  appears  from 
the  reports  of  Cohnheim,  Eberth,  and  Falkenthal,  in  which  the  disease 
lasted  from  11  days  to  4|  months,  and  in  which  microscopical  exami- 
nation showed  the  presence  of  lymphadenomatous  hyperplasia  of  the 
nodes  and  metastatic  growths  in  the  viscera.  These  cases  occurred  in 
children  under  15  years. 

2.  Chronic  pseudo-leukemia  may  suddenly  assume  a  grave  character 
and  prove  rapidly  fatal  from  the  ulceration  of  enlarged  lymph  follicles 
in  the  intestines,  as  first  shown  by  Berthenson's  cases,  and  now  not 
infrequently  verified  at  the  autopsy  table. 

3.  Acute  lymphosarcoma  may  run  a  rapidly  fatal  course  and  lead 
to  changes  in  the  viscera  which  are  very  similar  to  those  of  pseudo- 
leukemia. Fagge  collected  several  cases  to  illustrate  this  fact,  but 
their  real  ifature  is  not  always  apparent,  and  the  microscopical  reports 
were  meager.     They  were  all  attended  with  purpuric  symptoms. 

The  most  rapid  case  of  lymphosarcoma  that  the  writer  has  seen  lasted  four 
months.  The  nodes  showed  a  diffuse  growth  of  mononuclear  cells  much 
larger  than  Ij^mphocytes  and  few  giant  cells.  There  was  prompt  recurrence 
of  the  tumor  in  loco,  rapid  metastases,  marked  anemia,  and  no  leucocytosis. 
Much  more  rapidly  fatal  cases  have  been  observed,  while  Birch-Hirschfeld's 
case  of  true  Hodgkiu's  disease  following  typhoid  fever  was  fatal  in  6  weeks. 

Relation  of  Pseudo-leukemia  to  Leukemia. — The  identity  of  the 
process  in  the  lymphoid  tissues  in  pseudo-leukemia  and  leukemia  is 
strongly  indicated  by  the  histological  features  already  described. 

The  process  in  the  former  condition  differs  from  that  in  the  latter 
in  the  occlusion  of  lymph  vessels,  in  the  more  diffuse  and  abundant 
metastatic  growths,  usually  in  the  more  rapid  development,  often  in 
the  tendency  to  infiltrate  and  rupture  the  capsules,  in  the  lesser  ten- 
dency to  retrogressive  changes,  and  in  the  more  frequent  transformation 
into  giant-celled  lymphosarcoma. 

Pseudo-leukemia  may,  it  is  claimed,  lead  to  the  same  changes  in  the 
marrow  as  are  seen  in  lymphatic  leukemia.  (Perrin,  Schulz,  Dyren- 
futh,  Kelch,  Poufick,'  Schmuziger.) 

The  transformation  of  pseudo-leukemia  into  leukemia  has 
been  reported  in  several  cases.  Most  of  these  on  examination  prove 
to  be  of  uncertain  nature  or  were  undoubtedly  instances  of  terminal  or 
moderate  temporary  leucocytosis  in  the  course  of  some  disease  of  the 
lymph  nodes.  Only  three  of  these  cases  appear  to  be  genuine,  and  all 
refer  to  the  appearance  of  extreme  leucocytosis  during  the  course  of 
pseudo-leukemia. 

M osier  reports  an  acute  case  in  a  child  of  14  years,  whose  blood  a  few 
weeks  after  the  onset  of  the  disease  showed  no  leucocytosis,  while  about 


RELATION  OF  PSEUDO-LEUKEMIA    TO  TUBERCULOSIS.      227 

three  weeks  before  death  the  white  cells  were  as  numerous  as  the  red.  The 
varieties  of  cells  were  not  stated.  Senator  has  reported  a  case  of  trans- 
formation of  V.  Jaksch's  anemia  into  leukemia.  The  case  of  Fleischer  and 
Peuzoldt  is  the  most  significant.  Their  patient  was  a  male  of  40  years  who 
suffered  from  enlargement  of  many  lymph  nodes  for  16  months  before  death. 
Four  months  after  the  beginning  of  the  illness  there  was  no  leucocytosis,  but 
after  12  months  there  was  one  lymphocyte  to  eight  red  cells.  The  spleen 
was  moderately  enlarged,  the  lymph  nodes  extremely  large  ;  there  was  dif- 
fuse Ij'mphoid  infiltration  of  the  liver,  but  the  marrow  of  the  femur  Avas 
normal.     The  microscopical  structure  of  the  nodes  was  not  reported. 

It  thus  appears  that  the  statement  that  pseudo-leukemia  may  pass 
into  leukemia  rests  upon  the  observation  of  one  undoubted  case  only, 
in  which  the  report  meets  present  requirements,  and  that  one  was  pe- 
culiar in  other  respects.  The  more  recent  case  of  Posselt  is  an  ap- 
parently genuine  example  of  the  same  transformation  but  the  clinical 
history  is  meager.  The  remarkable  case  of  Lucke's,  of  lymphosarcoma 
with  rupture  into  a  vein  and  development  of  lymphatic  leukemia  is 
also  of  interest  in  this  connection.  One  must  therefore  accept  with 
considerable  reserve  the  opinion  that  some  forms  of  pseudo-leukemia 
represent  an  aleukemic  preliminary  stage  of  leukemia.  The  vast  ma- 
jority of  cases  of  pseudo-leukemia  pursue  a  chronic  course  showing  no 
tendency  to  develop  leukemia,  and  recent  experience  does  not  support 
Rothe's  belief  that  early  pleurisy  and  pneumonia  carry  off  many  cases 
of  pseudo-leukemia  before  the  leukemic  stage  has  had  time  to  appear. 
Eisenmenger  reports  a  case  of  pseudo-leukemia  which,  after  pursuing 
the  ordinary  course  for  four  years,  developed  malignant  tendencies  in- 
filtrating surrounding  tissues  and  perforating  the  larynx.  The  pres- 
ence of  90,000  leucocytes  in  this  case  would  have  led  many  observers 
to  suggest  the  presence  of  lymphatic  leukemia  as  well. 

Relation  of  Pseudo -leukemia  to  Pernicious  Anemia. — Runeberg 
reported  a  case  showing  pernicious  anemia,  which  he  regarded  as  an  ex- 
ample of  purely  myelogenous  variety  of  pseudo-leukemia,  on  account  of 
the  lymphoid  changes  in  the  marrow.  The  transformation  of  perni- 
cious anemia  into  pseudo-leukemia  was  claimed  to  have  occurred  in  a 
case  described  by  Laache,  and  there  can  be  no  doubt  that  the  marrow 
in  some  cases  of  pernicious  anemia  greatly  resembles  that  of  pseudo- 
leukemia, as  first  noted  by  Scheby-Buch,  and  Pepper.  On  evidence  of 
this  sort  Sevestre  suggested  that  all  cases  of  pernicious  anemia  fall  in 
the  class  of  pseudo-leukemia  but  this  view  cannot  be  supported  on  either 
clinical  or  anatomical  grounds. 

Relation  of  Pseudo-leukemia  to  Tuberculosis. — That  cases  of 
tuberculous  lymphadenitis  cannot  always  be  distinguished  clinically 
from  pseudo-leukemia  was  early  recognized,  and  so  commonly  observed 
that  the  scope  of  the  disease  was  by  some  widened  to  include  such 
cases.  Many  of  the  cases  of  so-called  chronic  intermittent  fever  with 
swelling  of  lymph  nodes  described  by  Pel,  Ebstein,^  Renvers,  and 
many  others,  probably  belong  in  this  class,  as  shown  by  Combemale. 

The  exact  significance  of  these  cases  appears  not  to  have  been  sus- 
pected  until  Askanazy  in  1888   demonstrated  tubercle  bacilli  in  the 


228  PSEUDO-LEUKEMIA. 

swollen  nodes  of  snch  a  case.  In  most  of  the  cases  in  which  micro- 
scopical examination  of  the  nodes  was  reported  there  were  distinct 
evidences  of  tuberculous  inflammation,  in  the  presence  of  miliary 
tubercles,  or  caseous  foci,  or  at  least  abundant  hyaline  degeneration, 
and  often  there  was  a  general  tuberculosis  (Delafield),  but  Waetzoldt's 
case  furnished  some  nodes  showing  pure  lymphoid  hyperplasia,  with 
onlv  very  scanty  and  minute  foci  of  hyaline  material,  although  coyitain- 
inq  many  tubercle  hacilll  in  seetions.  Finally  Brentano  and  Tangl  have 
described  a  chronic  case  in  which,  with  tuberculous  lesions  in  other 
regions,  the  lymph  nodes  showed  no  recognizable  evidences  of  tuber- 
culosis, not  even  minute  hyaline  areas,  nor  bacilli  in  section.  Inocu- 
lation experiments,  however,  demonstrated  the  tuberculous  nature  of  the 
process.     Sabrazes  has  reported  a  similar  case. 

On  this  evidence,  of  which  further  confirmation  appears  desirable, 
it  is  necessary  to  admit  either  that  (1)  tuberculosis  of  lymph  nodes  may 
follow  the  most  typical  course  of  acute  or  chronic  pseudo-leukemia,  or 
(2)  that  one  form  of  pseudo- leukemia  is  tuberculous,  or  (3)  that  tuber- 
culosis and  pseudo-leukemia  may  co-exist.  It  is  evident  also  that  mi- 
croscopical examination  of  lymph  nodes  is  not  a  sufficient  test  of  the 
tuberculous  nature  of  lymphomata,  and  that  the  entire  subject  requires 
readjustment  on  the  lines  indicated  above. 

That  all  cases  of  pseudo-leukemia  are  not  tuberculous,  however,  is 
shown  on  this  same  basis  by  the  negative  results  of  inoculation  ob- 
tained by  Westphal,  Sciola  and  Carta,  and  others. 

Infectious  Origin  of  Pseudo -leukemia. — Acute  or  chronic,  non- 
tuberculous,  in-flammatory  hyperplasia  of  lymph  nodes  may  reach  such 
extreme  degree  as  to  resemble  the  condition  found  in  pseudo-leukemia. 
The  reported  cases  of  this  character  are  numerous,  and  have  arisen 
from  a  great  variety  of  infections,  as  from  carious  teeth  (Ebstein,- 
Stengel),  quinsy  (Ponfick  '),  ulcerative  pharyngitis  (Chvostek),  typhoid 
fever  (Birch-Hirschfeld").  Other  cases  have  been  referred  to  otitis 
media,  chancroid,  eczema,  etc.  The  writer  has  seen  more  extensive 
lymphoid  hyperplasia  in  the  intestine  in  typhoid  fever  than  existed  in 
two  cases  of  pseudo-leukemia  dying  with  intestinal  ulcerations. 

Microscopical  examination,  where  reported,  has  shown  that  the  hy- 
perplasia of  nodes  is  inflammatory  in  character  and  not  lymphomatous, 
as  in  the  cases  of  Lannois  and  Courmont,  while  metastatic  growths  are 
wanting.  Many  of  these  cases  have  resembled  purpura  hemorrhagica, 
as  pointed  out  by  Kossler  and  regarded  by  him  as  evidence  of  infec- 
tious character. 

Lannois,  Courmont  and  Guillerraet  isolated  pyogenic  cocci  in  their 
cases.  The  occurrence  of  these  febrile  forms  of  the  disease  and  its  fre- 
quent development  after  many  cases  of  suppurative  inflammation,  espe- 
cially of  the  mucous  membranes,  early  suggested  the  idea  that  pseudo- 
leukemia is,  in  all  instances,  of  infectious  origin.  This  view  was 
reached  by  Westphal  after  a  full  review  of  the  subject  in  1893,  and 
has  since  been  maintained  by  Barbier,  Verdelli,  and  others.  Verdelli 
collected  fifteen  cases  of  pseudo-leukemia  in  which  the  presence  of  pyo- 


THE  CHANGES  IN  THE  BLOOD.  229 

genie  organisms  was  demonstrated  in  the  blood  or  lymph  nodes,  viz., 

Staphylococcus  jyi/ogenes  mireus,  7  times ;  Streptococcus  pyogenes,  3 
times  ;  pneumococcus  of  Frankel,  once  ;  unidentified  cocci  or  bacilli, 
four  times. 

Barbier  refers  the  failure  of  suppuration  in  these  cases  and  the  nega- 
tive results  of  some  inoculations  to  a  diminished  virulence  of  the  germ  or  to 
relative  insusceptibility  of  the  individual.  This  accumulating  evidence  points 
to  the  possibility  of  separating  from  true  pseudo-leukemia  a  considerable 
group  of  inflammatory  hyperplasias  of  bacterial  origin.  At  the  same  time  it 
must  be  admitted  that  the  micro-organisms  in  some  of  the  above  cases  were 
probably  the  cause  of  secondary  infectious  only,  and  there  are  opposed  to 
these  positive  results  of  culture  a  number  of  negative  reports. 

It  may  be  added  that  Lowit  claims  to  have  found  the  hemameba 
leukemice  magna  in  a  case  of  jjseudo-leukemia. 

Summary  of  Etiology. — It  thus  appears  that  the  group  of  cases 
now  regarded  as  falling  in  the  class  of  pseudo-leukemia  passes  by  in- 
sensible gradations  at  one  point  into  the  inflammatory  hyperplasias  of 
lymph  nodes,  at  another  into  the  true  lymphosarcomata,  and  at  another 
into  lymphatic  leukemia. 

The  field  may  undoubtedly  be  greatly  simplified  by  invariable  resort 
to  inoculation  to  demonstrate  the  presence  or  absence  of  tuberculosis. 
These  and  all  other  cases  of  inflammatory  origin  should  be  separated 
from  the  genuine  disease.  There  remains  a  considerable  number  of 
cases  in  which  the  clinical  character  of  the  disease  and  the  microscop- 
ical structure  of  the  nodes  resemble  those  of  sarcoma.  It  seems  best, 
as  suggested  by  Kundrat,  Dreschfeld,  and  others,  to  separate  such  cases 
also  from  the  others,  although  the  distinctions  between  frank  lympho- 
sarcoma and  pseudo-leukemia  are  not  sharply  drawn,  and  transitional 
stages  occur.  (Sharp.)  Likewise  the  increasing  number  of  apparently 
authentic  transformations  of  Hodgkin's  disease  into  lymphatic  leukemia 
strongly  suggests  a  close  relation  between  these  two  conditions.  The 
evidence  at  hand  seems  to  throw  lymphatic  leukemia,  pseudo-leukemia 
and  lymphosarcoma  into  a  single  group  possibly  connected  by  some 
common  etiological  factor. 

The  Changes  in  the  Blood. 

Red  Cells. — It  is  a  uniform  observation  that  in  the  early  stages  of 
pseudo-leukemia  the  anemia  may  be  very  slight.  The  red  cells  fre- 
quently number  five  millions  or  more,  when  the  nodes  are  distinctly 
swollen.  With  the  progress  of  the  lesion  there  is  usually  a  progressive 
loss  of  red  cells,  which,  however,  is  less  marked  than  in  corresponding 
stages  of  leukemia.  In  fatal  cases  there  may  be  surprisingly  little 
anemia,  usually  the  cells  fall  below  three  millions,  and  occasionally  the 
condition  of  the  blood  resembles  secondary  pernicious  anemia.  In 
acute  cases  the  anemia  may  rapidly  increase,  and  the  disease  resembles 
a  septic  infection  or  a  malignant  new  growth. 

In  morphology  the  red  cells  usually  show  the  changes  of  simple  secon- 
dary anemia  of  chronic  course.     Laache  has  called  attention  to  the 


230  PSEUDO-LEUKEMIA. 

very  uniform  size  of  the  red  cells  in  the  average  case.  In  some  of  the 
Avriter's  cases  the  cells  have  been  very  uniformly  undersized.  Later, 
megalocytes  deficient  in  Hb  may  appear,  but  they  are  seldom  numerous, 
and  do  not  lead  to  confusion  with  pernicious  anemia.  Laache  also  re- 
ports an  obscure  case  regarded  as  showing  the  transformation  of  perni- 
cious anemia  into  pseudo-leukemia. 

Nucleated  red  cells  are  usually  very  scarce,  even  in  late  stages,  and 
when  present  are  usually  of  moderate  dimensions.  Jawein  reports  an 
obscure  case  of  splenic  type,  and  afebrile  course,  in  which  there  were 
3^840-5,914  normoblasts.  The  condition  of  the  blood  resembled  that 
of  von  Jaksch's  anemia,  but  the  patient  was  an  adult. 

The  Hb  is  in  all  cases  diminished.  A  low  Hb-index  is  commonly 
seen  in  early  stages  or  with  slight  diminution  of  red  cells,  while  in  ad- 
vanced cases  with  marked  reduction  of  red  cells  the  Hb-index  is  usually 
higher.     These  characteristics  are  common  to  most  secondary  anemias. 

The  anemia  of  the  typical  case  of  Hodgkin's  disease  stands  in  an  in- 
termediate position  between  simple  secondary  and  pernicious  anemia. 
It  is  usually  much  less  marked  than  in  corresponding  stages  of  leu- 
kemia and  almost  never  approaches  the  type  of  pernicious  anemia.  On 
the  other  hand  it  is  usually  more  marked  than  the  general  condition  of 
the  patient  would  lead  one  to  suspect,  thus  differing  from  most  forms 
of  secondary  anemia.  As  Grawitz  has  pointed  out,  the  character  of 
the  blood  changes  offers  little  encouragement  of  the  tendency  to  find  in 
this  disease  a  condition  related  to  either  pernicious  anemia  or  leukemia. 

Leucocytes. — The  number  of  leucocytes  in  the  blood  is  considerably 
influenced  by  the  character  of  the  process  in  the  lymph  nodes.  In  the 
majority  of  cases  the  leucocytes  are  normal  or  diminished  in  number, 
and  there  is  a  tendency  toward  relative  lymphocytosis.  In  many  cases 
however  the  leucocytes  are  continuously  increased,  with  periods  of  well- 
marked  leucocytosis.  The  increase  of  white  cells  may  be  considerable 
but  does  not  pass  beyond  the  limits  of  inflammatory  leucocytosis,  50,- 
000-60,000.  Exceptions  to  this  rule  must  be  allowed  in  the  cases  of 
pseudo-leukemia  which  appear  to  have  passed  into  leukemia,  while  in 
Eisenmenger's  case,  which  passed  into  sarcoma,  there  were  90,000 
leucocytes.  A  few  eosins  are  commonly  seen  in  afebrile  cases,  while 
an  occasional  myelocyte  has  sometimes  been  encountered. 

The  cases  showing  few  white  cells  the  writer  has  found  to  be  usually 
the  chronic  ones  of  slow  progress  and  without  fever,  while  a  high  pro- 
portion of  poly  nuclear  cells  with  or  without  absolute  increase  usually 
belongs  to  the  more  rapid  or  the  febrile  cases.  Limbeck  finds  that 
when  the  polynuclear  cells  are  increased  the  nodes  usually  show  in- 
flammatory changes,  but  when  lymphocytosis  is  found  the  nodes  ap- 
proach more  to  the  sarcomatous  type.  In  lymphosarcoma  also,'  not 
simulating  pseudo-leukemia,  the  small  lymphocytes  may  be  very  nu- 
merous. The  writer  has  been  unable  to  find  any  features  in  the  blood 
distinguishing  between  pseudo-leukemia  and  frank  chronic  tuberculosis 
of  lymph  nodes. 

Diagnosis  of  Pseudo-leukemia. — 1.  From  myelogenous  or  pro- 


BIBLIOGRAPHY.  231 

noimced  lymphatic  leukemia  the  diagnosis  is  readily  accomplished  by 
the  examination  of  the  blood,  demonstrating  the  absence  of  character- 
istic leucocytosis. 

2.  From  less  pronounced  cases  of  lymphatic  leukemia  the  diagnosis 
may  not  in  every  instance  be  possible.  Usually  the  excess  of  leuco- 
cytes in  pseudo-leukemia  affects  the  polynuclear  type,  but  as  the  histo- 
logical structure  of  the  nodes  approaches  sarcoma,  tlie  lymphocytes 
may  be  greatly  increased. 

3.  From  tuberculosis  of  lymph  nodes  the  diagnosis  may  require 
microscopical  examination  of  the  nodes.  If  tuberculous,  these  may 
show  (a)  distinct  tuberculous  lesions,  miliary  tubercles  and  cheesy 
areas  ;  (6)  small  areas  of  hyaline  material  associated  with  demonstrable 
tubercle  bacilli ;  (c)  lymphoid  hyperplasia,  without  any  trace  of  distinct 
inflammatory  changes  and  without  bacilli  in  demonstrable  numbers. 
Such  nodes  should  be  tested  by  inoculation. 

4.  Non-tuberculous  inflammatory  hyperplasia  of  lymph  nodes  usu- 
ally causes  irregular  fever,  polynuclear  leucocytosis,  and  suppuration 
of  the  nodes.  It  is  quite  possible  that  some  pyogenic  infections  of 
lymph  nodes  may  run  the  course  of  subacute  pseudo-leukemia. 

5.  The  splenic  form  of  Hodgkin's  disease,  or  "  splenic  anemia/'  usu- 
ally follows  the  type  of  chronic  pseudo-leukemia  with  moderate  changes 
in  the  blood.  The  blood  in  splenic  anemia  may  be  indistinguishable 
from  that  of  old  malarial  cachexia,  and  the  latter  condition  has  been 
said  to  pass  into  the  former.  (Gowers.)  The  writer  has  found  the 
clinical  condition  of  splenic  anemia,  with  blood  changes  indistinguish- 
able from  pseudo-leukemia,  proven  at  autopsy  to  be  associated  with  : 

(a)  Syphilis  of  the  spleen  (gummata). 

(b)  Large  round-celled  sarcoma  of  spleen. 

(c)  Chronic  splenitis  of  the  type  of  epiilieliome  primitive  of  Gaucher. 
id)  Cellular  and  fibrous  stages  of  the  ordinary  lesion  of  the  spleen 

in  pseudo-leukemia. 

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Sabrazes.     Soc.  Anat.  et  Physiol,  de  Bordeaux,  Feb.  8,  1892. 

Scheby-Buch.     Deut.  Archiv  klin.  Med.,  Bd.  17. 

Schulz.     Archiv  f.  Heilkunde,  1874,  p.  200. 

Sehmtiziger.     Archiv  f.  Heilk.,  1876,  p.  279. 

Sdokb,  Carta.     Gaz.  d.  Osped.,  No.  5,  1894. 

Senator.     Berl.  klin.  Woch.,  1882,  p.  533. 

Sevestre.     Prog.  Med.,  1877,  No.  34. 

Sharp.     Jour,  of  Anat.  and  Phvsiol.,  Vol.  30,  p.  59. 

Stengel.     20th  Cent.  Pract.,  Vol.  II.,  pp.  445. 

Strumpel.     Archiv  f.  Heilk.,  1876,  Bd.  17,  p.  547. 

Trousseau.     Clinique  Med. 

Velpeau.     Lecons  Orales  de  Clinique,  T.  III. 

VerdeUi.     Archiv  Ital.  de  klin.  Med.,  1894,  T.  32,  4,  p.  595. 

Virchow.     Krank.  Geschwulste,  II. 

Waetzoldt.     Cent.  f.  inn.  Med.,  1890,  No.  45. 

Wagner.     Deut.  Archiv  klin.  Med.,  Bd.  38. 

Westphal.     Deut.  Archiv  klin.  Med.,  Bd.  51,  p.  83. 

Wilkes.     Guy's  Hosp.  Rep.,  1856,  p.  114. 

Woillez.     Soc.  med.  d.  Hop.,  1856. 

Wunderlich.     Archiv  f.  Physiol.  Heilk.,  1858,  p.  123. 


1 


CHAPTER   X. 

ANEMIA   INFANTUM   PSEUDO-LEUKEMICA. 
SPLENECTOMY. 

ANEMIA   INFANTUM    (V.    JAKSCH). 

Historical. — In  1889-90  von  Jaksch  described  a  form  of  infantile 
anemia  clinically  resembling  leukemia  but  failing  at  autopsy  to  show 
the  visceral  lesions  of  leukemia. 

The  disease  was  said  to  be  characterized  by  grave  anemia,  high  and 
persistent  leucocytosis,  marked  enlargement  of  the  spleen,  slight  swell- 
ing of  the  liver  and  occasionally  of  the  lymph  nodes,  and  was  to  be 
distinguished  from  leukemia  by  the  disproportionate  size  of  the  spleen 
as  compared  with  that  of  the  liver,  by  the  more  moderate  leucocytosis, 
by  the  more  favorable  prognosis,  and  by  the  absence  of  leukemic  infil- 
tration of  the  viscera. 

Peculiar  forms  of  grave  anemia  in  infants  had  previously  been  de- 
scribed by  Italian  observers,  Cardarelli,  Somma  and  Fede,  under  the 
term  "  infective  splenic  anemia."  Mosler  and  Senator  also  had  long 
before  recognized  and  described  numerous  cases  of  infantile  anemia 
which  they  placed  in  an  intermediate  position  between  leukemia  and 
pseudo-leukemia. 

Shortly  after  v.  Jaksch's  first  reference  to  this  condition  Hayem  de- 
scribed a  case  in  which  the  blood  contained  numerous  nucleated  red 
cells,  many  showing  mitotic  figures.  The  leucocytes  were  chiefly  mono- 
nuclear, but  the  eosins  were  increased.  In  Luzet's  case  nucleated  red 
cells  were  not  v^ery  numerous,  but  the  eosins  were  increased  and  some 
mitotic  leucocytes  were  seen. 

Thereafter,  reports  of  cases  multiplied  rapidly  so  that  in  1892 
Monti  and  Berggrun  were  able  to  collect  16  cases,  not  including  those 
of  Hausse  and  Loos,  and  added  four  of  their  own.  In  recent  years 
the  knowledge  of  the  condition  has  not  been  greatly  extended,  and 
opinions  regarding  its  significance  are  still  at  variance. 

Etiology. — The  typical  condition  is  usually  limited  to  infants  and 
children  between  one-half  and  four  years  of  age.  The  majority  of  the 
reported  cases  have  occurred  in  girls.  Rachitis  is  of  undoubted  im- 
portance in  the  disease  since  it  was  prominent  in  16  of  the  20  cases  of 
Monti  and  Berggrun.  In  the  cases  of  severe  rachitis  reported  by  Hock 
and  Schlesinger  ^  the  changes  in  the  blood  resembled  those  of  v.  Jaksch's 
anemia,  even  when  the  spleen  was  not  enlarged.  Syphilis,  chronic  in- 
testinal catarrh,  and  chronic  tuberculosis  were  found  in  other  cases,  col- 
lected by  Fischl. 

An  infectious  origin  was  held  for  very  similar  cases  as  early  as 


234  ANE3nA  INFANTUM  PSEUDO-LEUKEMICA. 

1880  by  Cardarelli,  and  in  1887  by  Somma  and  Fede.  Later  Mya 
and  Trambusti,  Toeplitz,  and  Gianturco  and  Pianese,  again  maintained 
the  infectious  nature  of  the  malady.  Kecently  Lowit  reports  finding 
the  "  hcmameba  leukemice  magna  "  in  one  case. 

Pathological  Anatomy. — The  changes  in  the  viscera  have  been  de- 
scribed principally  by  v.  Jaksch  (Eppinger),  Luzet,  Baginsky,  Aude- 
oud,  and  Rotch. 

The  spleen  is  much  enlarged,  and  usually  rather  firm.  Histologic- 
ally the  changes  are  those  of  simple  hyperplasia  of  all  elements,  while 
the  sinuses  contain  an  excessive  number  of  leucocytes.  Luzet  found 
some  mitotic  normoblasts,  but  in  his  cases  nucleated  red  cells  were  not 
numerous  in  the  blood.  Baginsky  found  many  eosinophile  cells  in  the 
spleen.  Audeoud  described  extensive  proliferative  changes  in  the 
splenic  follicles  and  pulp,  gorging  of  sinuses  with  leucocytes,  and  occa- 
sional extravasations  of  blood. 

The  liver,  in  the  majority  of  cases,  has  been  found  moderately  en- 
larged, usually  less  so  than  the  spleen,  and  of  uniform  color  and  normal 
consistence.  Luzet  could  not  verify  the  claim  that  the  liver  is  less  af- 
fected than  in  leukemia,  while  in  a  case  of  the  writer's  the  liver  was 
quite  as  large  as  in  fatal  cases  of  leukemia  in  young  children.  Histo- 
logically there  is  an  absence  of  leukemic  infiltration,  but  Luzet  found 
between  the  liver  cords  a  considerable  number  of  large  cells  (15-25  /j.  in 
diameter)  which  he  regarded  as  progenitors  of  the  red  blood  corpuscles. 

In  a  case  of  the  writer's,  examined  in  1896,  within  the  liver  capil- 
laries there  were  small  collections  of  nucleated  red  cells  and  leucocytes, 
of  which  some  of  both  were  found  in  mitotic  division,  but  the  charac- 
ters of  leukemic  infiltration  were  entirely  wanting.  The  infiltration 
with  these  groups  of  small  cells  gave  much  the  same  appearance  as  the 
late  fetal  liver.  In  the  fetal  liver,  however,  these  foci  are  composed 
almost  exclusively  of  nucleated  red  cells.  In  one  of  Rotch's  cases  also 
a  similar  condition  was  described. 

The  lymph  nodes  were  moderately  enlarged  in  12  of  20  cases,  but  in 
no  degree  comparable  to  the  changes  of  leukemia.  The  marrow  was 
described  by  Luzet  as  diflFusely  reddened  and  moist,  and  as  showing 
evidence  of  excessive  multiplication  of  red  cells. 

The  Changes  in  the  Blood. — The  red  cells  are  always  markedly 
diminished,  v.  Jaksch's  case,  in  which  they  numbered  820,000, 
showed  exceptionally  severe  anemia,  the  majority  of  cases  having  1.5- 
3.5  million  red  cells.  The  ordinary  changes  of  grave  secondary  anemia 
are  to  be  noted  in  the  red  cells.  Alt  and  Weiss  found  poikilocytosis 
very  prominent  in  their  cases,  but  this  condition,  together  with  mega- 
locytes  and  microcytes  deficient  in  Hb,  are  common  to  other  anemias. 

An  excessive  abundance  of  nucleated  red  celes  has  been 
shown  to  be  one  of  the  most  characteristic  features  of  the  blood  of  this 
condition,  in  which  they  may  be  even  more  numerous  than  in  leukemia. 
Yet  they  are  not  always  present,  in  which  case  the  disease  becomes 
difficult  to  distinguish  from  pseudo-leukemia.  Luzet,  Alt,  and  Weiss, 
and  others,  have  noticed  that  an  unusual  number  of  these  cells  are 


SIGNIFICANCE  OF  "  V.  JAKSCH'S  ANEMIA."  235 

found  in  mitotic  division.  In  well-marked  cases  the  nucleated  red 
cells  may  all  be  of  normal  size  for  this  age,  but  in  the  graver  stages  of 
anemia  megaloblasts  reach  a  considerable  proportion  or  a  majority. 
The  usual  degenerative  changes  in  the  red  cells  of  severe  anemia  have 
been  described  in  several  of  these  cases. 

The  leucocytosis  is  an  important  characteristic.  Usually  the  white 
cells  number  between  20,000  and  50,000,  but  in  an  apparently  genuine 
case  of  Baginsky's  they  varied  between  122,000  and  40,000.  In  more 
typical  cases  the  uniform  persistence  of  the  leucocytosis  without  marked 
variations  has  been  somewhat  peculiar.  Some  cases  have  recovered 
with  diminishing  leucocytosis. 

In  most  instances  in  wliich  differential  estimates  are  reported,  the 
mononuclear  cells  have  been  slightly  in  the  majority.  In  apparently 
genuine  cases  (Rotch,  Hock  and  Schlesinger ")  the  mononuclear  cells, 
large  and  small,  formed  80  percent,  84  percent,  and  75  percent,  of  a 
greatly  increased  number  of  leucocytes  (in  one  case  116,000).  In 
other  cases  the  poli/nuclear  cells  have  been  the  more  numerous.  The 
proportion  of  eosinophile  cells  varies.  Although  considerably  increased, 
up  to  6  percent  (Vickery),  they  do  not  reach  either  the  proportions  or 
numbers  seen  in  leukemia.  Myelocytes  have  been  noted  by  Klein  and 
in  the  more  recent  reports,  but  only  in  small  numbers.  In  one  of 
Vickery's  cases  10  percent  of  myelocytes  are  reported  among  22,000 
white  cells.  Usually  these  cells  are  not  so  abundant  as  to  suggest  leu- 
kemia. 

Great  variations  in  the  size  of  the  neutrophile  leucocytes  have  been 
described,  but  cannot  be  regarded  as  a  special  character.  The  great 
variety  of  degenerative  changes  seen  in  all  the  blood  cells,  especially  in 
the  leucocytes,  has  been  very  fully  described  and  depicted  by  Engel. 

Significance  of  "  v.  Jaksch's  Anemia." — The  attempt  to  determine 
the  true  nature  of  the  cases  described  under  this  term  must  be  guided 
by  the  known  characteristics  of  the  blood  of  infants.  The  more  im- 
portant of  these  characters  are:  (a)  The  relative  lymphocytosis ;  (b)  the 
more  active  leucocytosis  excited  by  chemotactic  influences  ;  (c)  the  tendency 
to  enlargement  of  the  spleen  in  all  chronic  anemias  of  infants ;  (d)  the 
hyperemia  of  the  mar  row  associated  with  rachitis  ;  {e)  the  facility  with  which 
blood  formation  in  infants  partially  irgresses  toward  the  embryonal  type. 

With  these  disturbing  factors  in  view,  it  would  appear  that  some  of 
the  reported  cases  of  anemia  pseudo-leukcniica  could  better  be  classed 
as  pernicious  anemia,  by  referring  the  peculiar  leucocytosis  to  the  spe- 
cial tendencies  of  infants'  blood.  Such  a  case  is  that  of  v.  Jaksch  in 
which  there  were  820,000  red  cells  and  54,660  leucocytes  of  undeter- 
mined varieties. 

Other  cases,  like  that  of  Rotch,  with  1,311,500  red  cells,  116,500 
leucocytes,  80  percent  lymphocytes,  enlarged  lympli  nodes,  no  autopsy, 
etc.,  might  perhaps  better  stand  as  a  case  of  lymphatic  leukemia  with 
unusual  proportion  of  nucleated  red  cells.  Yet  the  present  tendency 
is  to  accept  too  uncertain  evidence  in  the  diagnosis  of  lymphatic  leu- 
kemia, and  the  writer  agrees  with  Rotch  in   his  classification  of  this 


230  ANEMIA  INFANTUM  PSEUDO-LEUKEMICA. 

case.  One  of  Senator's  cases  also  showed  enlargement  of  lymph  nodes 
and  a  ratio  of  1-10  between  leucocytes  and  red  cells.  Likewise  Vick- 
ery's  case,  with  22,000  leucocytes,  35.8  percent  lymphocytes,  10  per- 
cent myelocytes,  and  6.2  percent  eosins,  and  no  autopsy,  may  have 
been  an  early  stage  of  myelogenous  leukemia,  but  myelemia  in  infants, 
even  if  acute,  ought  to  give  more  than  22,000  leucocytes  and  10  per- 
cent myelocytes,  while  if  chronic  its  characters  are  usually  unequivocal. 
The  real  nature  of  these  cases  must  remain  obscure  in  the  absence  of 
repeated  and  very  complete  examinations  of  the  blood,  and  microscopical 
study  of  the  viscera. 

Finally,  it  is*possible  that  many  of  the  cases  are  to  be  regarded  as 
grave  anemia  with  leueocytosis  of  peculiar  character.  This  view  is  sup- 
ported by  the  occasional  record  of  recoveries  and  of  gradual  transforma- 
tions into  grave  anemia  with  ordinary  leueocytosis.     (Monti,  Berggrun.) 

Nevertheless,  in  spite  of  the  resemblance  of  many  cases  to  pernicious 
anemia,  leukemia,  or  grave  anemia  with  leueocytosis,  there  appears  to 
be,  in  the  clinical  history,  in  the  morphology  of  the  blood,  and  especially 
in  the  condition  of  the  viscera,  sufficient  ground  on  which  to  separate, 
at  least  for  the  present,  certain  peculiar  forms  of  chronic  anemia  in 
children  from  any  of  the  above  conditions. 

In  the  clinical  history  these  signs  are,  chiefly,  the  chronic  course,  the 
frequent  association  with  rachitis,  syphilis,  or  chronic  intestinal  catarrh, 
the  pronounced  enlargement  of  the  spleen,  and  the  usual  absence  of 
distinct  features  of  pernicious  anemia,  leukemia,  or  of  a  cause  of  leu- 
eocytosis. In  the  blood  the  changes  are  rarely  such  as  to  cause  confu- 
sion with  pernicious  anemia,  though  the  condition  appears  at  times  to 
precede  pernicious  anemia.  While  the  acute  cases  with  many  lym- 
phocytes or  myelocytes  may  be  indistinguishable  from  leukemia  (one 
case  of  Luzet's  (XXV.)  having  passed  slowly  into  leukemia),  in  other 
more  numerous  instances  the  peculiar  condition  of  the  blood  persists 
unchanged  for  months  and  shows  no  tendency  to  declare  itself  as  leu- 
kemia. In  the  average  case  of  grave  secondary  anemia  the  leueocytosis 
fails  to  show  the  peculiar  characters  of  this  condition.  The  exces- 
sive numbers  of  nucleated  red  cells  and  the  very  active  multiplication 
of  these  cells  and  of  leucocytes,  as  indicated  by  the  large  proportion  of 
mitotic  nuclei,  and  the  abundance  of  myelocytes  and  eosinophile  cells, 
or  of  large  lymphocytes,  are  signs  not  necessarily  connected  with  grave 
anemia  in  children,  but  here  constitute  a  striking  and  distinctive  blood- 
picture. 

Considering  the  changes  in  the  viscera,  it  is  found  that  while  the  other 
features  of  the  disease  simulate  pernicious  anemia  or  leukemia,  there 
are  neither  the  leukemic  infiltrations  and  hyperplasias,  nor  the  exces- 
sive iron-content  of  the  liver,  or  the  megaloblastic  changes  in  the  mar- 
row, of  pernicious  anemia. 

The  Avriter  is  inclined  to  believe  that  the  peculiar  groups  of  mitotic 
red  cells  and  leucocytes  found  in  the  hepatic  capillaries  of  the  single 
case  which  he  has  had  opportunity  to  examine  may  indicate  the  essen- 
tial nature  of  the  condition.     The  presence  of  these  cells  shows  that 


BIBLIOGRAPHY.  237 

the  liver  had  resumed  or  retained  its  fetal  function  of  blood  cell  for- 
mation. Similar  groups  of  cells  resembling  leucocytes  have  been  de- 
scribed by  Rotch  and  similarly  interpreted,  but  without  mention  of 
Hb-content  or  mitotic  figures  in  the  cells.  Luzet  also  mentioned  the 
presence  of  peculiar  groups  of  cells  in  the  liver.  If  these  observa- 
tions can  be  verified,  a  specific  anatomical  condition  will  have  been 
established  for  v.  Jaksch's  anemia,  viz,  the  resumption  by  the  liver  under 
the  influence  of  grave  anemia  or  toxemia  of  its  fetal  function  of  de- 
veloping red  and  possibly  also  white  blood  cells.  The  conditions 
would  then  differ  from  pernicious  anemia  in  the  absence  of  extreme 
megaloblastic  changes  in  the  marrow,  and  in  the  extension,  rather,  of 
normoblastic  red  cell  formation  beyond  the  marrow  and  into  the  next 
most  available  tissue,  which  is  the  liver.  On  this  anatomical  basis  it 
would  still  be  impossible  to  explain  the  frequent  presence  of  many 
lymphocytes  or  myelocytes  which,  however,  may  be  referred  to  the  co- 
incident affection  of  lymphoid  tissues,  especially  of  the  marrow,  a  tis- 
sue which  in  this  disease  has  as  yet  received  inadequate  attention. 

In  a  case  observed  by  the  writer  in  1896  the  patient  was  a  markedly 
rachitic  infant  of  20  months.  The  spleen  extended  3  inches  below  the  costal 
border.  The  liver  was  considerably  enlarged.  The  lymph  nodes  were  not 
enlarged.  The  red  cells  numbered  1,820,000,  about  10  percent  of  which 
were  pale  megalocytes.  Nucleated  red  cells  were  extremely  abundant  and 
usually  of  normal  size.  Hb  not  taken.  The  leueocj'tes  numbered  48,000, 
of  which  22  percent  were  small  lymphocytes,  34  percent  large  lymphocytes, 
3  percent  myelocytes,  38  percent  polynuclear,  3  percent  eosins. 

The  spleen  was  the  seat  of  uniform  hyperplasia  of  pulp  cells,  while  the 
follicles  were  much  reduced  in  size  and  number.  Throughout  the  pulp  there 
were  numerous  small  collections  of  small  cells  with  compact  or  mitotic 
nuclei.  Many  of  these  were  nucleated  red  cells.  Mitotic  leucocytes  were 
not  identified.  There  was  beginning  increase  of  connective  tissue  and  the 
sinuses  were  often  obliterated.  Eosins  were  very  abundant.  The  livei-  ex- 
hibited numerous  small  intracapillary  foci  of  cells,  many  of  which  contained 
mitotic  nuclei.  Of  these  the  majority  were  nucleated  red  cells,  others  were 
much  larger  and  granular.  Occasionally  they  appeai'ed  fused  together  in 
one  cell  mass,  resembling  the  multinuclear  masses  of  Luzet.  These  groups  of 
cells  resembled  the  foci  of  nucleated  red  cells  of  the  embryonal  liver,  but 
were  much  less  numerous.     The  liver  cells  were  not  fatty. 

The  marrow  of  the  femoral  shaft  was  cellular  throughout,  no  fat  cells 
being  found  in  this  situation  which  in  normal  subjects  of  this  age  is  at  least 
partly  fatty.  There  was  general  hyperplasia  of  cellular  elements,  but  the 
cells  were  not  densely  packed  as  in  leukemia.  The  islands  of  nucleated  red 
cells  were  very  numerous,  th?se  cells  being  distinctly  in  excess.  Many 
mitotic  leucocytes  with  granular  protoplasm  were  identified.  The  sinuses 
were  obliterated.  Eosins  were  not  over  abundant.  The  condition  of  the 
spleen,  liver,  and  marrow  indicated  that  excessive  demands  were  being 
made  upon  the  blood-forming  organs,  and  that  these  demands  were  being 
met  by  the  marrow,  the  liver,  and  probably  also  by  the  spleen. 

Bibliography. 

Anemia  Infantum. 
Alt,  WeUs.     Cent.  f.  med.  Wissen.,  1892,  Nos.  24-25. 
Amleond.     Kevuc  nie^d.  de  la  Suisse  Rom.,  1894,  p.  507. 
Bagimky.     Arcliiv  f.  Kinderheilk,  1892,  Bd.  13,  ]>.  304. 
Cdrtlarelli.     Atti  d.  priino  Cong.  Pediatr.,  Naples,  1891. 


238  SPLENECTOMY. 

Engel.     Yircliovr's  Arcbiv,  Bd.  135,  p.  369. 

Fede.     Atti  d.  priiiio  Cong.  Pediatr.,  Naples,  1891. 

Fischl.     Zeit.  f.  Ileilk.,  1892,  Bd.  13,  277. 

Gianturco,  Pianese.     Uaz.  d.  Clin.,  Naples,  1892,  III.,  p.  305. 

Hausse.     Diss.  Miinchen,  1890. 

Hayem.     Gaz.  des  Hop.,  1889,  No.  30. 

Hock,  Schlesincjer.     '  Beitnige  zur  Kinderheilk.  Wien.,  1892.     K'ent.  f.  klin.  Med., 

1891. 

r.  Jaksch.     Wien.  klin.  Wocli.,  1889,  Nos.  22-23.     Prager  med.  Woch.,  1890,  No. 


99 


'Klein.     Berl.  klin.  Woch.,  1890,  No.  31. 
Loos.     Wien.  klin.  Woch.,  1891,  p.  26. 
Lowit.     Die  Leukemic  als  Protozoeninfec.  Wiesbaden,  1900. 
Luzd.     Archiv  gen.  de  Med.,  1891,  I.,  p.  579.     These  de  Paris,  1891. 
Monti,  Berggrun.     Die  chron.  Anemie,  etc.,  Leipsic,  1892. 
Master.     Cited  by  Senator. 
Mya,  Trambusti.     Lo  Sperimentale,  1892. 
Botch.     Pediatrics,  Philadelphia,  1897,  p.  359. 
Senator.     Berl.  klin.  Woch.,  1882,  p.  533. 
Somma.     Allg.  Wien.  med.  Zeit.,  1891,  Nos.  4-11.^ 
Toeplitz.     Jahrbuch  f.  Kinderheilk.,  Bd.  33,  p.  367. 
Vickery.     Med.  News,  1897,  Vol.  71,  p.  731. 

SPLENECTOMY. 

The  effects  of  spleaectoray  upon  man  are  usually  the  combined  re- 
sults of  severe  hemorrhage,  or  preexisting  anemia,  of  the  loss  of  the 
function  of  the  organ,  and  very  often  of  intravenous  infusion  practiced 
immediately  after  the  operation. 

How  much  of  these  effects  are  referable  solely  to  the  loss  of  the 
organ  can  better  be  determined  by  comparing  the  blood  changes  fol- 
lowing splenectomy  in  animals  with  those  observed  in  the  human  sub- 
ject. 

Effects  of  Splenectomy  in  Animals. 

Hosier  was  one  of  the  first  to  study  the  effects  of  splenectomy  upon 
healthy  dogs.  He  found  a  diminution  of  red  cells,  persisting  for  several 
months,  but  no  changes  in  the  leucocytes.  The  blood-forming  function, 
then  regarded  as  inherent  in  the  spleen,  he  believed  to  have  been  trans- 
ferred to  the  marrow,  in  which  tissue  he  found  changes  comparable  to  those 
of  leukemia.  The  chief  permanent  chemical  alteration  he  found  to  be  a 
loss  of  iron.  Malassez  found  the  oligocythemia  to  persist  only  one  month, 
while  the  Hb  remained  deficient  much  longer.  Zesas  found  in  rabbits  a 
marked  leucocytosis,  reaching  a  maximum  in  the  tenth  week,  when  the  red 
cells  begin  to  diminish.  The  blood  was  restored  to  the  normal  six  months  after 
the  operation.  Winogradoff  found  that  the  red  cells  in  dogs  diminish  for 
200  days,  and  many  megalocytes  appear.  Irf  the  second  year,  smaller  cells 
reappear  and  the  total  number  gradually  becomes  normal.  In  two  of  three 
dogs  there  was  considerable  leucocytosis.  Diminution  of  specific  gravity  and 
of  Hb  was  constantly  noted.  The  lymph  nodes  of  the  animals  were  found  to 
be  smaller,  and  the  marrow  hyperemic.  Gibson  found  the  maximum  diminu- 
tion of  red  cells  60  days  after  splenectomy  (three  dogs).  Pronounced  leucocy- 
tosis was  observed  the  day  after  the  operation.  The  restoration  of  the 
blood  required  six  months. 

More  recently  Kourloflf  followed  the  course  of  the  leucocytosis  of  splenec- 
tomy, finding,  in  the  fir.st  year  following  the  operation  varying  grades  of 
lymphocytosis,  the  proportion  of  these  cells  rising  from  30  up  to  60  percent. 
The  proportion  of  granular  leucocytes  fell  from  40-50  percent  to  20  percent, 
or  less.     The  numbers  of  large  mononuclear  cells  did  not  change,  indicating 


SPLENECTOMY  IN  MAN.  239 

that  the  spleen  cannot  be  considered  as  their  place  of  origin  During  the 
second  year,  a  prominent  alteration  of  the  blood  was  a  marked  eosinophilia, 
while  in  this  period  the  lymphocytes  fell  to  the  normal  proportion. 

Emlianoff  demonstrated  in  splenectomized  dogs  a  slight  diminution  of  red 
cells  and  an  extreme  leucocytosis  marked  by  an  initial  loss  of  small  cells,  and 
a  sudden  increase  of  larger  (polynuclear)  cells.  Vulpius  also  observed  in 
several  rabbits  a  moderate  leucocytosis  lasting  not  longer  than  nine  weeks, 
and  a  loss  of  20  percent  in  the  number  of  red  cells,  which  were  restored 
within  five  to  six  weeks. 

It  has  therefore  been  show^n,  by  the  above  observers  among  others, 
that  splenectomy  in  animals  is  followed  by  moderate  reduction  in  red 
cells  lasting  from  one  to  twelve  months,  by  relatively  greater  loss  of 
Hb  more  slowly  restored,  and  in  some  cases  by  the  appearance  during 
the  first  year  of  raegalocytes. 

Leucocytosis  follows  the  operation,  but  its  extent  and  duration  are 
very  variable.  A  polynuclear  leucocytosis  is  observed  during  the  first 
days  or  weeks,  followed  by  relative  or  absolute  lymphocytosis  during 
the  first  year,  while  during  the  second  year  distinct  eosinophilia  may 
be  observed. 

With  these  changes  in  the  blood  are  associated  a  marked  cellular 
hyperplasia  of  the  marrow,  approaching  at  times  that  of  leukemia,  and 
often  also  afiFecting  the  lymph  nodes.  In  the  SAVollen  nodes  an  exces- 
sive number  of  nucleated  red  cells  have  been  foimd  by  Winogradoff, 
Tizzoni,  Gibson,  Kourloif,  and  Grunberg. 

Splenectomy  in  Man. 

The  most  marked  changes  in  the  blood  following  splenectomy  in 
man  are  seen  in  those  cases  in  which  the  organ  has  been  removed  for 
rupture  or  idiopathic  enlargement.  Successful  cases  are  recorded  by 
Czerny,^  Regnier,  Hartley,  McBurney,  and  others.  In  Czerny's  case 
of  idiopathic  enlargement  (1,500  grm.)  the  Hb  fell  to  56  percent,  while 
the  red  cells  were  very  slightly  reduced  and  reached  over  5  millions 
within  a  month,  but  four  years  later  the  patient,  for  reasons  not  stated, 
was  foimd  to  have  only  3.3  million  red  cells  with  85  percent  of  Hb. 
The  leucocytosis  was  very  marked,  reaching  70,000  within  a  week  and 
persisting  for  at  least  eight  weeks. 

In  Regnier's  case  of  rupture  of  spleen  with  severe  hemorrhage,  the 
Hb  fell  to  20  percent,  rising  gradually  to  80  percent  in  the  eighth 
week.  The  red  cells,  falling  to  2.5  millions,  rose  to  4.7  millions  by 
the  eighth  week.  An  acute  leucocytosis,  25,000,  appeared  soon  after 
the  operation.  One  month  later  the  polynuclear  cells  had  been  largely 
replaced  by  an  equal  number  of  lymphocytes.  Nucleated  red  cells 
and  eosins  were  scarce. 

Hartley's  case  (examined  by  the  writer)  was  complicated  by  infu- 
sion, and  possibly  by  preexisting  malaria.  The  anemia  on  the  fourth 
day  was  profound  ;  the  leucocytosis  was  extreme,  estimated  roughly  at 
75,000,  of  which  77  percent  were  polynuclear.  Many  "  splenocytes  " 
and  a  moderate  number  of  myelocytes  with  deficient  neutrophile  gran- 


240  SPLENECTOMY. 

ules,  and  a  few  normoblasts,  were  present,  so  that  the  blood  strikingly 
resembled  that  of  leukemia.  At  the  end  of  three  weeks  the  young 
patient's  blood  had  greatly  improved,  and  the  leucocytes  were  normal. 
After  three  months  the  only  abnormality  was  the  presence  of  a  few  mod- 
erate-sized megalocytes,  and  an  apparent  deficiency  of  neutrophile  gran- 
ules. Later  examinations,  extending  over  three  years,  failed  to  show, 
at  any  time,  an  absolute  increase  of  either  lymphocytes  or  eosins,  or  any 
persistent  anemia. 

In  McBurney's  case  the  writer  found  the  anemia  and  the  resemblance 
to  leukemic  blood  even  more  pronounced.  The  same  prompt  improve- 
ment followed,  and  six  months  later  the  blood  was  practically  normal. 

After  splenectomy  for  various  other  general  indications  not  includ- 
ing malaria  and  leukemia,  rather  variable  results  have  been  noted.  In 
the  cases  collected  by  Vulpius,  Hartley,  and  Litten,  and  reviewed  by 
various  authors,  the  writer  finds  a  general  resemblance  of  the  blood 
changes  when  reported  to  those  described  after  experimental  splenec- 
tomy. The  grade  of  anemia  and  the  period  required  for  the  restora- 
tion of  the  blood  seem  to  vary  with  the  general  condition  of  the  patient 
and  the  circumstances  of  the  operation.  Dominici  describes  a  case  in 
a  tuberculous  subject  in  whose  blood,  1 2  days  after  the  operation,  a 
very  large  number  of  nucleated  red  cells  began  to  appear,  9,800  per 
ccm.  having  been  counted  at  one  time.  After  three  weeks  they  dis- 
appeared. 

In  the  majority  of  the  cases  of  splenectomy  for  wamlenng  spleen  and 
other  conditions  not  seriously  affecting  the  patient's  health,  the  blood 
was  described  as  normal  before  and  after  the  operation,  but  in  some 
the  usual  reduction  of  red  cells  and  leucocytosis  have  been  observed. 
The  slight  changes  commonly  noted  are  probably  referable  to  the 
effects  of  the  laparotomy,  as  Hartraann  and  Vaquez  found  that  after 
every  such  operation  there  is  slight  anemia  and  leucocytosis. 

The  malarial  spleen  has  been  excised  by  many  surgeons  with 
favorable  results.  Jonnesco,  who  reports  a  series  of  cases,  found  a 
prompt  increase  of  red  cells  after  a  temporary  diminution  (.5-2  mil- 
lions) and  a  somewhat  persistent  leucocytosis  (15,000-30,000).  The 
operation  affected  a  prompt  cure  of  long-persistent  cachexia.  Similar 
favorable  results  were  obtained  by  Hartley,  Vulpius,  and  others. 

In  letikemia  the  spleen  has  been  extirpated  in  28  cases  with  im- 
mediately fatal  results  in  25.  One  case  survived  13  days,  another  8 
months,  and  a  third,  in  which  the  diagnosis  must  be  doubted  (Franzo- 
lini,  1882),  was  reported  cured.  In  the  two  genuine  cases  the  opera- 
tion was  followed  by  steady  diminution  of  red  cells  and  increase  of 
leucocytes.     (Bardenhauer,  Burckhardt.) 

Visceral  Changes  Following  Splenectomy. — Enlargement  of  lymph 
nodes  has  been  observed  after  splenectomy  in  man  by  Czerny,^  Kocher, 
Lennander,  and  Regnier.  In  Regnier's  case  the  enlargement  of  the 
nodes  was  associated  with  lymphocytosis.  The  marrow  was  examined 
by  Regnier  four  weeks  after  the  splenectomy  and  found  very  hyper- 
emic.     There  had  been  marked  anemia  in  this  case. 


BIBLIOGRAPHY.  241 

Resume. — In  comparatively  healthy  subjects,  splenectomy  has  often 
been  performed  without  affecting  the  blood  more  than  does  any  other 
laparotomy. 

In  many  graver  cases  the  loss  of  blood  and  the  shock  of  the  opera- 
tion give  rise  to  a  considerable  grade  of  secondary  anemia.  The  red 
cells  are,  in  favorable  cases,  restored  in  1-3  months,  but  in  less  favor- 
able cases  there  may  be  more  persistent  anemia.  The  restoration  of 
Hb  seems  in  some  cases  to  fall  behind  the  improvement  in  cells  rather 
more  than  in  most  secondary  anemias.  The  operation  is  usually  fol- 
lowed by  considerable  polyuuclear  leucocytosis  (15,000—50,000),  which 
commonly  persists  for  2—6  weeks,  but  may  continue  for  months,  in 
which  case  the  polyuuclear  cells  may  be  largely  replaced  by  lympho- 
cytes. Eosinophilia  has  been  observed  in  a  few  cases  during  the 
second  and  third  years. 

In  traumatic  cases  suffering  from  large  hemorrhages,  splenectomy, 
especially  when  complicated  by  infusion,  may  lead  to  very  profound 
anemia,  marked  by  extreme  loss  of  red  cells,  the  presence  of  many 
very  large,  pale,  sometimes  polychromatic,  and  dissolving,  red  cells, 
nucleated  red  cells,  and  to  a  high  grade  of  leucocytosis.  Among  the 
leucocytes  there  may  be  a  considerable  proportion  of  large,  pale  mono- 
nuclear cells  and  myelocytes,  so  that  the  blood  resembles  that  of  acute  leu- 
kemia. This  condition  however  is  transitory  and  the  blood  may  im- 
prove rapidly. 

Leukemia  and  the  amyloid  spleen  are  contraindications  to  splenec- 
toDiy.  In  other  conditions  the  choice  of  operation  may  depend 
entirely  upon  the  general  condition  of  the  patient.  Beyond- a  moderate 
persistent  leucocytosis  or  lymphocytosis,  and  possibly  a  slight  delay  in 
the  restoration  of  Hb,  there  are  no  specific  effects  known  to  follow 
splenectomy  in  man. 

Bibliography. 

Splenectomy. 

Bardenhauer.     Deut.  Zeit.  f.  Chir.,  Bd.  45,  p.  181. 
Burckhardt.     Archiv  f.  klin.  Chir.,  Bd.  43,  p.  446. 
Czerny.     i  Cited  by  Vulpius.     ^  wien.  raed.  VVoch.,  1879,  p.  333. 
Dominki.     Compt.  Rend.  Soc.  Biol.,  1898,  p.  1193. 
Emilianoff.     Archiv  des  Sci.  Biol.,  St.  Petersburg,  Bd.  II.,  No.  2. 
Fmnzolini.     Gaz.  med.  Ital.,  1882,  Guil. 
Gibson.     Jour,  of  Anat.  and  Physiol.,  1886,  Vol.  20,  p.  674. 
Grunherg.     Diss.  Dorpat,  1891. 
Hartley.     Med.  News,  1898,  Vol.  72,  p.  417. 
Hartman,   Vaquez.     Compt.  Rend.  Soc.  Biol.,  1897,  p.  126. 
Jonnesco.     Archiv  f.  Sci.  med.  (Bucharest),  1897,  p.  301. 
Koeher.     Cent.  f.  Chir.,  1889,  p.  14. 

Kourloff.     Wratsch,  1889,  1892,  cited  by  Ehrlich,  Die  Anemie. 
Lennander.     Wien.  klin.  Woch.,  1893,  No.  30. 
Malassez.     Gaz.  med.  de  Paris,  1878,  p.  317. 
McBurney.     N.  Y.  Med.  Record,  Vol.  53,  p.  601. 
Mosler.     Leukemia,  1872. 
Regnier.     Berl.  klin.  Woch.,  1893,  p.  181. 
Tizzoni.     Archiv  Ital.  de  Biol.,  1882,  T.  1. 
Vulpius.     Beitriige  zur  klin.  Cliir.,  1894,  Bd.  11. 

Winogradoff.     Cited  by  Laudenbach,  Archiv  de  Physiol.,  1896,  p.  724. 
Zesas.     Langenbeck's  Archiv,  Bd.  28,  p.  157. 
16 


PART  III. 
THE  ACUTE  INFECTIOUS  DISEASES. 

INTRODUCTORY   SECTION. 
THE   BLOOD    IN   FEVER. 

While  all  observers  have  agreed  that  the  blood  in  fever  suffers  a 
reduction  in  red  cells,  it  still  remains  a  matter  of  doubt  whether  a  fe- 
brile process  alone  actually  destroys  red  cells  or  only  causes  them  to 
be  unequally  distributed  in  the  body. 

The  theory  of  unequal  distribution  of  red  cells  in  the  acute  fevers 
is  supported  by  a  variety  of  observations.  Maragliano  demonstrated 
a  contraction  of  arterioles  during  the  height  of  a  febrile  process,  fol- 
lowed by  dilatation  during  defervescence,  and  he  was  able  to  verify 
these  results  by  watching  the  effects  of  antipyretics.  Breitenstein 
found  an  excess  of  red  cells  in  the  livers  of  heated  animals  coincident 
with  a  deficiency  in  peripheral  vessels,  while  Naunyn  under  the  same 
conditions  could  find  no  evidence  of  destruction  of  red  cells.  Increase 
in  specific  gravity  of  the  blood  was  demonstrated  by  Stein,  with  ris- 
ing temperature,  followed  by  lowering  of  gravity  in  defervescence. 
Reinert  believes  that  excessive  loss  of  fluids  diminishes  the  volume  of 
blood  during  the  height  of  the  fever,  while  retention  of  fluids  results 
from  lower  blood  pressure  and  heart  weakness  after  defervescence. 
Tumas  believes  that  the  blood  in  fever  may  be  reduced  in  bulk  as  well 
as  in  proportion  of  red  cells. 

In  favor  of  the  view  that  the  red  cells  are  destroyed  in  fever  is  the 
demonstration  of  an  excess  of  potassium  (Salkowski),  and  of  hydro- 
bilirubin  (Gerhardt,  Hoppe-Seyler)  in  the  urine.  Yet  Bunge  has 
shown  that  the  red  cells  which  are  very  rich  in  potassium  may  take  up 
and  discharge  large  amounts  of  this  element  without  themselves  being 
destroyed.  In  pure  types  of  experimental  pyrexia  Naunyn  and  others 
have  found  no  solution  of  Hb  in  the  blood-serum  and  no  evidences  of 
destruction  of  red  cells.  Werhowsky,  however,  exposed  rabbits  to  a 
temperature  of  38.5-40°  C.  for  2-29  days  and  found  a  steady  diminu- 
tion, reaching  30  percent,  of  Hb,  followed  by  progressive  loss  of  red 
cells,  moderate  leucocytosis,  and  deposits  of  hemosiderin  in  the  marrow 
and  spleen.  Similar  indications  were  obtained  long  ago  by  Mobitz  in 
septic  animals  whose  blood  at  first  showed  from  day  to  day  consider- 
able variations  in  the  red  cells  but  eventually  a  permanent  loss. 

These  results  leave  no  doubt  of  the  capacity  of  prolonged  fever  to  de- 


244  THE  ACUTE  INFECTIOUS  DISEASES. 

stroy  red  cells,  but  the  length  of  time  re(ju'ired  furnishes  opportunity  for 
factors  other  than  pyrexia  to  intervene.  Consequently  Lowit  ^  concludes 
that  the  real  nature  of  the  oligocythemia  in  early  febrile  process  is 
still  doubtful. 

Fever  is  usually  accompanied  by  marked  disturbance  of  the  coagula- 
tion of  the  blood,  which  has  sometimes  been  found  increased,  at  others 
diminished  or  entirely  inhibited.  From  the  studies  of  Schmidt  and  his 
pupils  it  has  been  shown  that  in  septic  fever  coagulation  is  diminished 
at  an  early  stage  and  increased  at  another  later  stage.  The  variations 
depend,  according  to  Bojanus,  upon  changes  in  the  quantity  either  of 
fibrinoplastic  substances  or  of  fibrin  ferment,  and  are  connected  with 
the  presence  of  dissolved  Hb  in  the  plasma.  In  non-febrile  pyrexia, 
insolation,  the  coagulability  of  the  blood  is  lost. 

Changes  in  Chemical  Composition. — A  progressive  loss  of  albumens 
of  the  blood  in  febrile  diseases  has  been  noted  by  many  observers,  but 
it  is  not  yet  known  whether  the  loss  is  referable  to  the  pyrexia  or  to 
other  associated  factors. 

While  there  is  good  reason  to  believe  that  the  less  diffusible  globulin 
should  suffer  less  than  the  albumen,  as  Gottschalk  claims  to  have  found 
in  some  instances,  yet  Limbeck  and  Pick  found  that  no  general  rule 
could  apply  to  variations  in  the  globulin  of  the  blood  in  infectious 
diseases.  A  contrary  conclusion  also  was  reached  by  Emmerich  and 
Tsuboi  who  found  the  globulin  of  the  blood  to  diminish  when  rabbits 
are  being  immunized  against  hog  cholera. 

Resistance  of  Red  Cells  in  Fever. — A  diminished  resistance  of  the  red 
cells  and  increased  isotonic  tension  of  the  plasma  were  demonstrated  by 
Maraffliano  in  severe  anemia,  and  bv  Celli  and  Guarnieri  in  various 
fevers,  while  the  morphological  characters  which  indicate  this  change 
in  the  red  cells  have  been  described  by  Maragliano,  Gabritschewsky, 
and  Grawitz.  Yet  diminished  resistance  of  the  red  cells  is  not  found 
in  all  fevers  and  may,  as  Limbeck '  has  shown,  be  at  times  increased. 
While  Hamburger  has  shown  that  the  resistance  of  the  red  cells  de- 
pends principally  upon  the  osmotic  tension  of  the  plasma,  Demoor 
refers  the  low  resistance  in  fever  to  the  presence  in  the  blood  of  bac- 
terial toxines  and  of  excess  of  CO^,  while  Lowit  ^  connects  it  more 
closely  with  changes  in  the  vessel  walls. 

Febrile  Hydremia. — A  marked  diminution  of  the  albumens  of  the 
plasma  has  been  demonstrated  in  many  infectious  diseases  by  Hammar- 
schlag,  Limbeck,^  Biernacki,^  Wendelstadt,  and  others,  and  has  been 
referred  not  to  increase  in  the  total  bulk  of  water  in  the  blood  but  to 
destruction  of  albumens  in  the  febrile  process.  Herz  believes  further 
that  the  febrile  hydremia  is  characterized  also  by  swelling  of  the  red 
cells  with  corresponding  oligoplasmia,  and  Limbeck  and  Steindler 
found  the  volume  of  the  serum  in  three  healthy  subjects  to  average 
72.6  percent,  while  in  eight  acute  febrile  cases  it  fell  to  an  average  of 
54.8  percent.  On  the  other  hand  Pfeiffer  denies  that  the  red  cells 
swell  in  febrile  diseases,  finding  rather  that  they  shrink,  and  Biernacki 
denies  the  existence  of  any  uniform  febrile  hydremia.     The  conclusions 


THE  BLOOD  IN  FEVER.  245 

of  each  of  the  above  observers  appear  to  be  justified  by  their  results, 
and  their  conflicting  opinions  must  be  referred  to  technical  errors  or  to 
particular  conditions  existing  in  the  subjects  of  their  study. 

Alkalescence. — Abundant  sources  of  acid  metabolic  products  are 
believed  to  exist  in  fever  as  a  result  of  imperfect  oxidation  of  albumens 
and  the  formation  thereby  of  fatty  and  lactic  acids,  as  well  as  in  the 
■development  of  acids  as  a  result  of  bacterial  growth.  Numerous  obser- 
vations, also,  by  Senator,  v.  Jaksch,  Kraus,  Klemperer,  et  ciL,  have 
apparently  shown  by  different  methods  that  febrile  processes  are  regu- 
larly marked  by  diminished  alkalescence  of  the  blood.  Yet  Minkowski 
has  from  the  first  pointed  out  that  at  the  height  of  the  fever  the  loss  of 
alkalescence  is  not  proportional  to  the  pyrexia.  Limbeck  and  Steindler 
in  a  large  series  of  febrile  subjects  found  in  both  blood  and  serum 
variations  in  alkalescence  quite  within  normal  limits. 

On  the  other  hand  Lowy  and  Richter,  using  a  special  method  which 
they  claim  to  be  more  reliable  than  others,  find  that  in  a  certain  period 
•of  febrile  processes  corresponding  to  the  stage  of  hypoleucocytosis  the 
blood  shows  an  increase  and  not  a  decrease  of  alkalescence.  The  cause 
of  this  condition  is  not  yet  explained,  but  Lowy's  results  have  been 
verified  by  Lowit,  Biernacki,-  and  Strauss. 

Important  contributions  to  the  subject  were  made  by  Fodor  and 
Rigler.  These  observers  found  that  the  serum  of  rabbits  infected  with 
anthrax  at  first  shows  an  increase  of  alkalescence,  but  after  24  hours  a 
rapid  and  marked  diminution.  With  rabies  the  alkalescence  dimin- 
ished from  the  first.  Between  the  quantity  of  diphtheria  toxin  injected 
and  the  final  loss  of  alkalinity  therefrom  they  found  a  parallel.  In- 
jections of  vaccine  increased  the  alkalescence  for  7— S  days,  of  diph- 
theria antitoxin,  for  only  48  hours.  Since  the  alkalinity  of  the  serum- 
ash  did  not  vary  with  that  of  the  serum  they  concluded  that  the 
property  depends  on  the  presence  of  organic  substances.  Other  im- 
portant studies  of  the  alkalescence  of  the  blood  by  Cantani,  Calabrese, 
etc.,  have  shown  that  the  important  variations  in  the  quality  of  the 
blood  are  dependent  less  upon  fever  than  upon  other  obscure  chemical 
processes. 

Lowit^  concludes  that  the  alkalescence  of  the  blood  may  be  increased  at 
one  thne  and  diminished  at  another  period  of  an  infectious  disease,  that 
this  property  is  not  dependent  in  any  large  measure  upon  the  leucocytes 
and  that  its  sic/nijicance  is  still  unexplained. 

Action  of  Bacteria  and  their  Products  on  the  Blood. — Many  of  the 
phenomena  classed  among  the  effects  of  fever  on  the  blood  can  be  di- 
rectly traced  in  part  to  the  action  of  bacteria  and  bacterial  products 
which  are  the  exciting  causes  of  the  febrile  process. 

Bouchard  has  demonstrated  for  the  bodies  of  Bacillus  pyocyaneus, 
and  Gley  and  Charrin  for  their  filtered  products,  a  vaso-constricting 
action,  and  therefore  a  tendency  to  concentrate  the  blood.  An  in- 
•creased  flow  of  lymph  and  probably  a  similar  concentrating  effect  upon 
the  blood  has  been  shown  to  follow  the  injection  into  animals  of  pep- 
tone and  animal  extracts,  by  Heidenhain,  of  tuberculin,  pyocyanin, 


246  THE  ACUTE  INFECTIOUS  DISEASES. 

pneumotoxin,  by  Gartner  and  Romer.  Rapid  variations  in  the  gravity 
of  the  blood  have,  in  Grawitz's  ^  hands,  followed  the  injection  of  cul- 
tures of  cholera,  diphtheria,  and  pyogenic  organisms.  Small  doses  of 
toxines  of  various  bacteria  were  found  by  Bianchi  and  Mariotti  to  in- 
crease the  isotonic  tension  of  the  blood  quite  beyond  normal  limits, 
while  large  doses  of  many  germs  or  even  small  injections  of  Bacillus 
typhosus  had  the  opposite  effect. 

Specific  bacterial  products,  toxalbumius,  bacterio-proteins,  and  pto- 
maines, are  believed  by  most  observers  to  be  the  active  agent  in  the 
destruction  of  the  albumens  of  blood  and  tissues  in  infectious  diseases, 
acting  at  times  without  the  accompaniment  of  fever.     (Muller.) 

As  a  specific  elFect  of  the  chemotactic  action  of  bacteria  and  their 
products  upon  the  white  blood  cells  there  is  the  whole  series  of  phe- 
nomena of  leucocytosis,  the  significance  of  which  is  considered  in  an- 
other section. 

Conclusions  Regarding  the  Blood  in  Fever. — From  the  foregoing  brief 
review  it  will  be  seen  that  the  changes  in  the  blood  in  fever  form  an 
extremely  complex  subject,  about  which  our  knowledge  is  still  rather 
fragmentary.  The  same  phenomena  have  been  encountered  in  differ- 
ent lines  of  investigation  and  attributed  to  different  single  factors, 
though  probably  referable  to  many.  While  some  main  facts  are  rather 
distinctly  apparent,  other  questions  must  remain  undecided  until  fully 
adequate  technical  methods  are  devised. 

Decrease  or  relative  increase  in  the  proportion  of  red  cells,  but  end- 
ing always  in  a  loss  in  their  total  numbers,  must  be  accepted  as  accom- 
panying all  cases  of  pyrexia,  although  requiring  some  time  to  become 
clearly  apparent. 

Coagidab'ility  varies  in  different  stages  of  febrile  diseases,  but  is  not 
clearly  connected  with  the  pyrexia  as  such. 

The  progressive  loss  of  albumen  of  the  blood  is  probably  essentially 
connected  with  the  febrile  process,  but  occurs  in  increased  degree  when 
the  fever  is  of  infectious  origin. 

Febrile  hydremia  is  an  accidental  condition  which  may  or  may  not 
occur  as  a  result  of  the  loss  of  albumens  of  the  blood.  Diminished  re- 
sistance of  red  cells  occurs  in  the  majority  of  fevers,  and  depends  on  a 
variety  of  factors.  Variations  in  alkalinity  are  frequent  and  consider- 
able in  fever,  but  are  not  proportional  either  to  the  height  of  the  tem- 
perature or  to  the  toxic  condition  of  the  blood. 


Bibliography. 

Blood  in  Fever. 

Blancld,  Mariotti.     Wien.  med.  Presse,  1894,  No.  36. 

Biernacki.     iZeit.  f.  klin.  Med.,  Bd.  24.     2 Ibid.,  Bd.  .31,  p.  312. 

Bojanus.     Inaug.  Diss.  Dorpat,  1881. 

Bouchard.     Lecons  sur  les  Autointoxications,  Paris,  1887. 

Breitenstein.     Archiv  f.  exper.  Path.,  Bd.  18,  p.  42. 

Bunge.     Zeit.  f.  Biol.,  Bd.  9,  p.  129. 

Calabrese.     Policlinico,  1896,  fasc.  1,  2. 

Cantani.     Cent.  f.  Bact.,  Bd.  20,  p.  556. 


BIBLIOGRAPHY.  247 

Celli,  auarnierl     Fort.  d.  Med.,  1889,  No.  14. 
Demoor.     Jour.  med.  de  Bruxelles,  1896,  No.  36. 
Emmerich,  Tsuboi.     XI.  Cong.  f.  inn.  Med.,  1892,  p.  202. 
Fodor,  Rigler.     Cent.  f.  Bact.,  Bd.  21,  p.  134. 
Gabritschewsky.     Arcliiv  f.  exper.  Path.,  Bd.  28,  p.  83. 
Gartner,  Romer.     Wien.  klin.  Woch._,  1892,  No.  2. 
Gerhardt.     Ueber  Hydrobilirubin,  Diss.  Berlin,  1889. 
Gley,  Charrin.     Cent.  f.  Bact.,  1894,  p.  688. 
Gottschalk.     Zeit.  f.  physiol.  Chem.,  Bd.  12,  cited  by  Limbeck. 
Orawitz.     'Zeit.  f.  klin.  Med.,  Bd.  22,  p.  411. 
Hamburger.     Virchow's  Archiv,  Bd.  140,  p.  503. 
Hammarschlag.     Zeit.  f.  klin.  Med.,  Bd.  21,  p.  475. 
Herz.     Virchow's  Archiv,  Bd.  133. 
Hoppe-Seyler.     Virchow's  Archiv,  Bd.  124,  p.  30. 
V.  Jaksch.     Zeit.  f.  klin.  Med.,  Bd.  13. 
Kraus.     Zeit.  f.  Heilk.,  Bd.  10. 

Limbeck     iKlin.  Path,  des  Blutes,  1896,  p.  158.     2  Prager  med.  Woch.,  1893,  Nos. 
12-14. 

Limbeck,  Steindler.     Cent.  f.  inn.  Med.,  1895,  p.  649. 

Lowit.     '  Die  Lehre  V.  Fieber.     2 Ibid.,  p.  151.     3 ibid.,  p.  164. 

Louy,  Bichter.     Deut.  med.  Woch.,  1895,  No.  33. 

Maragliano.     Berl.  klin.  Woch.,  1887,  No.  43. 

Minkowski.     Archiv  f.  exper.  Path.,  Bd.  19,  p.  215. 

Mobitz.     Inaug.  Diss.  Dorpat,  1883,  cited  by  Lowit. 

Midler.     Zeit.  f.  klin.  Med.,  Bd.  16,  p.  496. 

Naunyn.     Archiv  f.  exper.  Path.,  Bd.  18,  p.  81. 

Pfeiffer.     Cent.  f.  inn.  Med.,  1895,  No.  4. 

Reinerl.     Zahlung  d.  Blutkorp,  p.  174. 

Schmidt.     Pfliiger's  Archiv,  Bd.  11,  pp.  291,  515. 

Senator.     Untersuch.  u.  d.  lieberhaften.  Process,  Berlin,  1873. 

Stein.     Cent.  f.  klin.  Med.,  1892,  No.  23. 

Strauss.     Zeit.  f.  klin.  Med.,  1896,  Bd.  30,  p.  315. 

Tumas.     Deut.  Archiv  klin.  Med.,  Bd.  41,  p.  323. 

Wendelstadt.     Zeit.  f.  klin.  Med.,  Bd.  25. 

Werhowsky.     Cong.  f.  inn.  Med.,  1895,  p.  345. 


CHAPTER   XI. 
PNEUMONIA.     DIPHTHERIA. 

PNEUMONIA. 

The  gross  characters  of  the  blood  in  pneumonia  were  accurately 
described  by  Piorry,  who  noted  the  prompt  and  firm  clotting  due  to 
excess  of  fibrin,  while  the  distinct  crusta  phlogMica,  most  marked  about 
the  seventh  or  eighth  days,  was  the  earliest  recorded  observation  con- 
cerning the  leucocytosis  of  this  disease.  Fibrin  has  since  been  shown 
to  be  abundant  in  nearly  all  cases  of  pneumonia,  and  very  much  in- 
creased in  the  great  majority.  The  excess  often  continues  beyond 
defervescence.  In  very  severe  cases  without  leucocytosis,  fibrin  is  usu- 
ally deficient.     (Turk.^) 

The  total  volume  of  blood  is  probably  somewhat  reduced  in  severe 
cases  of  pneumonia,  owing  to  the  concentration  which  occurs  in  fever, 
from  cyanosis,  and  from  the  loss  of  cells  and  plasma  in  the  exudate. 
Evidences  of  this  concentration  have  accumulated  from  several  sources, 
among  which  are  :  the  increase  in  specific  gravity  during  the  height  of 
the  process  (Monti,  Berggrun),  and  the  persistence  of  a  high  propor- 
tion of  red  cells  and  Hb  which  usually  continues  until  the  crisis,  after 
which  there  is  a  rapid  decline  in  the  quality  of  the  blood. 

Large  exudations  into  the  lungs  are  believed  by  Bollinger  to  reduce 
the  quantity  of  blood  to  such  an  extent  that  oligemia  may  usually  be 
noted  at  autopsy.  In  65  percent  of  his  cases  marked  diminution  of 
blood  was  thus  noted  at  the  post-mortem  examination,  a  loss  which  was 
fully  explained  by  the  extent  of  the  exudate,  which  averaged  over  1,000 
gr.  in  weight. 

The  Red  Cells. — Although  destruction  of  red  cells  undoubtedly 
occurs  in  the  disease,  as  shown  by  the  increased  excretion  of  hydrobili- 
rubin,  and  the  occasional  appearance  of  jaundice,  yet  the  red  cells  re- 
main high  during  the  active  febrile  period,  when  this  destruction  is 
taking  place,  to  diminish  only  when  the  temperature  begins  to  fall. 
This  result  can  be  referred  only  to  the  concentrating  effects  of  fever, 
exudation,  and  local  vasomotor  phenomena,  and  is  to  be  seen  in  other 
infectious  fevers. 

In.  spite  of  these  complicating  factors  the  red  cells  usually  show  a 
slight  but  steady  decline  during  the  course  of  the  fever,  as  shown  by 
the  reports  of  Sorensen,  Boeckman,  Halla,  Tumas,  Sadler,  and  others. 

Slight  polycythemia  (maximum  7  millions)  frequently  appears  in  the 
reports  of  Sadler,  while  Sorensen  observed  an  inorease  of  red  cells  dur- 
ing the  febrile  period  in  one  case.     The  decrease  of  red  cells  often 


LEUCOCYTES.  249 

occurs  suddenly  with  the  crisis,  Tumas  reporting  one  case  with  a  fall 
of  600,000  on  the  day  of  defervescence.  The  diminution  continues 
for  a  very  variable  period  depending  upon  somewhat  complex  factors, 
but  commonly  ceases  within  10-14  days,  or  in  mild  cases  much  sooner. 

The  grade  of  anemia  established  is  usually  not  very  marked.  In 
many  recorded  estimates  the  loss  of  cells  did  not  exceed  the  limit  of 
error.  A  loss  of  .5—1  million  is  not  uncommon,  while  a  reduction  of 
2  million  cells  is  recorded  by  several  observers.  Such  changes  in  the 
red  cells,  however,  must  be  interpreted  with  great  caution.  There 
was,  for  instance,  a  loss  of  2  million  cells  in  one  of  Sadler's  cases,  yet 
no  anemia  was  established  as  the  blood  had  been  concentrated  and  the 
lowest  count  was  5.1  millions. 

Morphological  changes  in  the  red  cells  are  usually  slight.  Polychro- 
masia  is  seen  in  the  severe  cases  only. 

Nucleated  red  cells  were  present  in  7  of  Turk's  18  cases. 
These  were  usually  normoblasts,  occasionally  megaloblasts.  The  cases 
Avere  all  very  severe,  but  only  one  of  the  seven  was  fatal.  A  similar 
phenomenon  may  occur  in  other  severe  infections. 

The  Hb  suifers  considerably  more  than  the  red  cells,  being  almost 
invariably  reduced  after  defervescence,  but  in  the  absence  of  complica- 
tions seldom  falling  below  65  percent. 

Chemistry. — The  specific  gravity  was  found  to  remain  normal  or  to 
distinctly  increase  during  the  febrile  period  in  9  children  studied  by 
Monti  and  Berggrun.*  The  albumens  of  the  blood  were  slightly 
diminished,  while  those  of  the  serum  were  normal  or  increased  in  7  cases 
reported  by  v.  Jaksch.' 

The  to.viciti/  of  the  blood  serum  was  found  much  increased  in  pneu- 
monia and  other  infectious  diseases  by  Albu,  who  locates  the  poisonous 
principle  in  the  albumens  of  the  serum. 

Leucocytes. — Leucocytosis  appears  in  the  great  majority  of  cases 
of  pneumonia,  failing  only  in  very  mild  attacks  and  in  very  severe  in- 
fections with  feeble  reaction  and  bad  prognosis,  and  when  some  pre- 
existing conditions  have  already  excited  leucocytosis  or  debilitated  the 
system.  In  leukemia  a  complicating  pneumonia  reduces  the  leuco- 
cytes, while  the  onset  of  pneumonia  in  the  course  of  some  infectious 
diseases  is  not  always  traceable  in  the  blood. 

Although  the  leucocytosis  of  pneumonia  was  noted  by  Virchow, 
Nasse,  and  other  early  writers,  its  closer  study  was  begun  by  Sorensen 
in  1876,  and  continued  by  Boeckman,  Halla,  Tumas,  Hayem,  and 
Limbeck.^ 

Even  Boeckman  (1881)  gathered  from  the  literature  that  most  febrile  dis- 
eases are  accompanied  by  levicocytosis  and  that  typhoid  fever  and  malaria 
are  exceptions  to  the  rule.  Halla  noted  that  the  leucocytosis  is  not  pro- 
^  portional  to  the  fever,  having  encountered  three  cases  without  leucocytosis, 
all  fatal.  Hayem  and  Limbeck  followed  the  course  of  the  leucocytosis  over 
considerable  periods,  pointed  out  relations  between  the  grade  of  leucocytosis 
and  the  severity  of  the  disease,  discussed  the  time  and  manner  of  its  disap- 
pearance, and  reported  other  fatal  cases  without  leucocytosis. 

Limbeck's  study  was  especially  minute  and  he  was  able  to  detect  a  fall  in 


250  PNEUMONIA.     DIPHTHERIA. 

the  leucocy  tosis  some  hours  before  the  crisis,  and  to  note  the  absence  of  any 
change  during  pseudo  crises.  He  drew  the  important  general  deduction 
that  leucocytosis  precedes  and  is  a  part  of  the  inflammatory  exudate,  and 
that  non-exudative  diseases  are  unaccompanied  by  leucocytosis.  Rieder,  in 
1892,  was  probably  the  first  to  demonstrate  that  the  leucocytosis  of  pneu- 
monia is  not  determined  by  the  height  of  the  fever,  or  the  extent  of  the 
exudate,  but  depends  upon  the  intensity  of  the  infection  and  the  degree  of 
resistance  of  the  subject,  and  this  view  was  fully  supported  shortly  afterward 
in  the  writer's  series  of  cases. 

Since  Limbeck's  study,  the  leucocytosis  of  pneumonia  has  been  a  favorite 
field  of  investigation,  so  that  an  extensive  literature  in  many  languages  has 
accumulated,  and  many  interesting  and  important  details  have  been  added 
to  the  knowledge  of  the  subject. 

Course  of  the  Leucocytosis. — Leucocytosis  appears  very  early 
in  the  course  of  pneumonia,  simultaneously  with  the  chill,  according  to 
Klein,  preceding  the  exudation,  according  to  Limbeck,  and  having  re- 
peatedly been  found  on  the  first  day  of  the  disease.  In  one  of  the 
writer's  cases  25,000  cells  were  counted  within  4  hours  after  the  begin- 
ning of  the  first  symptom,  a  sharp  chill,  while  liieder  and  Laehr  found 
a  marked  increase  within  6  hours  of  the  chill.  Theoretically  the  leu- 
cocytosis should  be  preceded  by  a  period  of  hypoleucocytosis,  but  this 
period  has  never  been  observed  clinically,  except  in  fatal  cases  with 
prolonged  hypoleucocytosis. 

The  maximum  increase  is  reached  usually  just  before  the  crisis 
(Hayem,  Klein,  Bieganski),  but  has  been  observed  on  the  first  day  of 
the  disease,  or  on  succeeding  days.  AVhen  the  leucocytes  increase 
slowly,  they  usually  diminish  slowly,  and  the  disease  defervesces  by 
lysis.  Peculiar  cases  of  marked  severity  in  which  there  was  no  dis- 
tinct leucocytosis  until  the  temperature  began  to  fall,  are  reported  by 
Bieganski  and  Turk. 

During  the  high  febrile  movement  there  is  usually  little  alteration 
in  the  leucocytosis,  but  extension  of  the  lesion  to  other  lobes,  or  to  ad- 
joining serous  membranes,  may  cause  irregular  rises  in  the  count.  Yet 
in  a  case  in  which  bronchial  breathing  passed  successively  up  one  side 
of  the  chest  and  down  the  other,  the  writer  found  rather  uniform  and 
high  leucocytosis. 

A  few  hours  before  or  after  crisis  the  leucocytes  begin  to  diminish 
rapidly,  sometimes  falling  from  a  high  to  a  normal  figure  witiiin 
twenty-four  hours,  after  which  there  are  commonly  some  slight  oscil- 
lations. During  lysis  the  reduction  of  leucocytes  usually  keeps  pace 
with  the  temperature,  but  Limbeck's,  Laehr's,  and  Billings'  '  charts 
show  some  marked  upward  curves  of  the  leucocytes  after  lysis.  Such 
rises  are  most  often  due  to  complications.     (Kuhnau.') 

In  fatal  cases  there  is  often  a  continuous  increase  (Pick),  but  some- 
times the  leucocytes  are  high  at  first,  but  steadily  diminish  as  the  pa- 
tient grows  worse  (Bieganski,  Rieder),  while  in  many  fatal  cases  there 
is  no  leucocytosis.  Hayem  believed  that  in  fatal  cases  without  leuco- 
cytosis, the  lesion  is  "  less  exudative,"  but  subsequent  reports  have 
shown  this  view  to  be  inapplicable  to  the  majority  of  cases.  Alcohol- 
ism, virulent  infection,  and  old  age  are  more  important  factors.     In 


LEUCOCYTES. 


251 


four  such  cases  of  the  writer's  the  lesion  was  of  the  usual  type.  In 
one  of  these,  although  the  exudate  was  considerable,  the  marrow  of  the 
ribs  and  vertebrae  failed  to  show  the  usual  hyperplasia. 

Pseudo-crises  usually  have  no  effect  upon  the  leucocytosis  (Limbeck, 
Klein,  Laehr,  Bieganski),  but  Turk  and  others  have  shown  that  this 
is  not  an  invariable  rule. 

The  grade  of  leucocytosis  is  usually  considerable,  and  is  affected 
by  several  factors.  Hay  em  found  in  mild  cases  6,000—12,000  leuco- 
cytes, in  moderately  severe  cases  18,000-20,000,  and  in  very  severe 
cases  a  maximum  of  36,- 

000.     In  children  the  in-  Fig.  21. 

crease  is  usually  greater 
than  in  adults.  (Monti, 
BerggruUjFelsenthal.)  Se- 
vere uncomplicated  cases 
often  show  50,000  cells, 
while  some  writers  have 
found  purulent  complica- 
tions with  many  of  the  high 
leucocytoses,  especiall}' 
when  the  temperature  is 
relatively  low.  (Smith.) 
The  highest  figures  appear 
to  be  115,000,  recorded  by 
Laehr,  in  a  peculiar  case 
with  delayed  resolution. 
The  fever  and  the  leucocy- 
tosis often  run  parallel, 
but  there  are  numerous  in- 
dividual exceptions  to  this 
general  rule,  the  most  sig- 
nificant of  which  are  the 
fatal  cases,  showing  norma  1 
or  diminished  leucocytes. 
The  extent  of  the  exudate 
has  considerably  more  in- 
fluence upon  the  leuco- 
cytes,   as  first    shown    by 

Limbeck.       Although  con-  -Temperature. 

.  °  Leucocytosis. 

trary  conclusions  have  been  course  of  leucocytosis  in  pneumonia.  (After  Laehr. ) 

reached    by  many  writers 

reviewing  short  series  of  cases,  it  nevertheless  remains  true  that  the  leuco- 
cytosis in  general  bears  a  rather  close  relation  to  the  extent  of  the  exu- 
date. In  the  writer's  cases,  especially  in  those  which  came  to  autopsy, 
this  rule  was  readily  verified,  although  its  application  to  individual  cases 
proved  unsafe.  Thus  in  63  cases  in  which  one  lobe  was  afiected,  the 
average  number  of  leucocytes  was  20,000,  in  24  cases  with  the  two 
lobes  involved,  22,700,  in  12  cases  with  three  lobes,  25,000,  in  one 


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252  PNEUMONIA.     DIPHTHERIA. 

case  with  four  lobes,  27,000,  and  in  one  in  which  there  was  bronchial 
breathing  over  the  entire  back  of  chest,  32,000.  In  10  cases  with 
lesions  extending  to  the  pleura  (empyema),  pericardium  and  peritoneum, 
the  average  was  17,000,  a  tendency  toward  hypoleucocytosis  beginning 
to  appear. 

The  degree  of  systemic  reaction  to  the  disease  chiefly  determines  the 
grade  of  leucocytosis.  This  view,  first  clearly  stated  by  Rieder,  has 
been  fully  verified  by  many  observers,  and  embodies  the  true  meaning 
of  leucocytosis  in  infectious  diseases.  In  47  cases  marked  by  vigorous 
systemic  reaction  (temperature  105°,  full  pulse,  sthenic  condition),  the 
writer  found  an  average  of  30,000  leucocytes ;  in  27  moderate  cases 
(temperature  below  105°,  symptoms  less  severe),  the  average  was 
20,000  ;  in  27  cases  with  deficient  reaction,  9,000,  while  in  12  asthenic 
cases  the  leucocytes  were  subnormal. 

The  significance  of  hypoleucocytosis,  observed  in  many  fatal  cases,  has 
been  demonstrated  in  various  experimental  infectious  like  those  studied  by 
Tschistowitch,  who  found  that  rabbits  die  without  leucocytosis  when  inocu- 
lated with  virulent  cultures  of  the  pueumococcus,  but  with  attenuated  cul- 
tures there  is  leucocytosis,  and  the  animals  usually  recover. 

Types  of  Leucocytes  in  Pneumonia. — At  the  height  of  nearly  all  well- 
marked  leucocytoses  in  pneumonia  the  polynuclear  neutrophile  cells 
form  80-95  percent  of  the  cells.  Turk  counted  as  high  as  96.5  per- 
cent of  these  cells,  and  they  arc  frequently  above  90  percent.  This  high 
proportion  may  be  seen  when  the  leucocytosis  is  slight  or  absent,  but 
is  usually  most  marked  when  the  white  cells  are  very  numerous.  At 
the  same  time  there  is  a  marked  reduction,  relative  or  often  absolute, 
of  lymphocytes  to  2—4  percent.  The  large  mononuclear  cells  usually 
persist  in  considerable  numbers  (Turk),  may  sometimes  be  distinctly 
increased  (Klein),  and  are  never  entirely  absent  (Jez). 

The  eosinophile  cells  at  the  height  of  the  leucocytosis  are  always 
very  scanty  and  frequently  cannot  be  found  after  very  prolonged 
search.     (Zappert,  Turk.) 

Instead  of  polynuclear  leucocytosis  tliere  may  be  well-marked  lym- 
phocytosis, as  in  a  case  reported  by  Cabot,  in  which  in  a  chikl  of  6 
years  there  were  66  percent  of  lymphocytes  among  94,600  white  cells. 
Stienon  refers  to  similar  cases,  and  the  writer  and  others  have  observed 
such  inflammatory  lymphocytoses  in  diphtheria. 

During  defervescence,  the  polynuclear  cells  diminish  rapidly,  usually 
to  a  high  normal  proportion,  at  which  they  are  apt  to  remain  several 
days.  The  lymphocytes  at  the  same  time  increase  in  proportion,  and 
often  in  numbers,  reaching  their  normal  figures  also  after  a  few  days. 
The  large  mononuclear  leucocytes  are  usually  over-abundant  at  this 
stage,  reaching  16  percent  in  one  of  Turk's  cases,  and  constituting  the 
"  large-celled  lymphocytosis "  described  by  Klein  at  this  period. 
Eosinophile  cells  usually  reappear  in  scanty  numbers  on  the  day  before 
defervescence,  or  rarely  a  day  earlier.  (Turk.)  Distinct  post-critical 
eosinophilia  occurs  in  a  moderate  proportion  of  cases  (Zappert,  Bie- 
ganski),  but  not  in  all  (Turk). 


PLATE    X. 


Fig.   1. 


;r :  fe:  4Y  \ 


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Mast   Cells.     (Ehrlich's    Dahlia-stain.) 


Fig.  2. 


^•^ 

^ 


Glycogenic    Degeneration   of  Leucocytes   (Pneunnoniai. 
(Iodine  in    Mucilage   of  Acacia.) 


LEUCOCYTES. 


253 


In  severe  cases  without  leucocytosis,  the  polynuclear  cells  are  usually 
relatively  increased  (Rieder),  but  may  be  normal  (Billings).  Very 
often  in  such  cases  there  is  a  moderate  leucocytosis  during  or  after 
defervescence.     (Laehr.) 

Degenerativ,e  Changes  in  Leucocytes  in  Pneumonia. — Klein 
described  numerous  "leucocyte-shadows"  in  severe  pneumonia.  They 
are  seen  in  other  infectious  diseases,  especially  diphtheria,  and  are  to 
be  classed  with  the  degenerative  changes  in  tissue  cells  which  mark  the 


Fig.  22. 


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Temperature. 
Leucocytosis. 


Precritical  leucocytosis  in  pneumonia.     (After  Limbeck.) 

status  infectiosus.  Glycogen  granules  in  the  leucocytes  have  been  found 
in  considerable  abundance  by  Livierato  and  others,  usually  in  propor- 
tion to  the  severity  of  the  disease  and  the  height  of  the  leucocytosis. 

Myelocytes  Avere  found  by  Turk  in  nearly  all  cases.  They  were  most 
abundant  about  the  time  of  defervescence,  and  once  reached  a  propor- 
tion of  11.9  percent  among  8,800  cells. 

Peculiar  lymphocytes  of  large  or  small  size,  with  single  or  double 
nuclei,  staining  densely  and  with  a  brownish  tinge  by  the  triacid  mix- 


254  PNEUMONIA.     DIPHTHERIA. 

ture,  are  described  by  Turk  as  of  frequent  occurrence,  and  as  resulting 
from  abnormal  stimulation  of  blood-forming  tissues. 

Applications  in  Diagnosis  and  Prognosis. — The  very  numerous  situa- 
tions in  which  the  examination  of  the  blood  is  of  great  value  in  the 
diagnosis  of  pneumonia  have  been  pointed  out  by  numerous  writers. 
It  is  especially  in  such  acute  uncomplicated  infections  that  the  results 
of  examination  of  the  blood  are  to  be  relied  upon,  but  even  here  a 
word  of  warning  is  needed  against  too  implicit  confidence  in  this  or 
any  other  isolated  clinical  sign,  ichUe  it  is  especial/ 1/  iinicise  to  transfer  to 
other  fields  in  blood  analysis  the  rather  positive  rules  ichich  may  usually 
be  applied  to  the  changes  in  the  blood  in  pneumonia. 

Barring  mild  cases,  and  those  fatal  ones  in  which  there  is  no  increase 
of  white  cells,  leucocytosis  is  an  invariable  accompaniment  of  pneu- 
monia, and  its  absence  is,  therefore,  very  strong  negative  evidence 
against  pneumonia. 

When  present,  leucocytosis  excludes,  with  somewhat  less  certainty, 
a  considerable  class  of  diseases  which  are  not  usually  accompanied  by 
leucocytosis.  These  are  principally  typhoid  and  typhus  fevers,  ma- 
laria, acute  tuberculous  pneumonia,  uncomplicated  influenza,  and  the 
catarrhal  pneumonia  of  influenza.      (Rieder.) 

In  prognosis  a  slight  leucocytosis  indicates  a  mild  case,  while  in  se- 
vere cases  a  low  proportion  of  leucocytes  is  an  extremely  unfavorable 
prognostic  sign.  This  fact  was  first  pointed  out  by  Kikodse  and  v. 
Jaksch,  although  such  cases  had  previously  been  reported  by  Halla 
and  Hayem.  Yet  absence  of  leucocytosis  appears  not  to  be  so  unfavor- 
able as  was  at  first  supposed.  Out  of  57  severe  cases  without  leuco- 
cytosis, reported  by  Halla,  Hayem,^  Laehr,  Ewing,  Sadler,  Bieganski, 
Zappert,  Turk,  Billings,  Cabot,  only  44  died,  although  all  of  them 
were  unusually  severe  cases. 

The  persistence  of  leucocytosis  may  be  of  value  in  distinguishing 
pseudo-crises,  but  Bieganski,  Turk,  and  others  have  seen  the  leuco- 
cytes fall  during  a  pseudo-crisis. 

Continuous  or  increasing  leucocytosis  after  defervescence  often  indi- 
cates a  relapse  or  complication. 

The  reappearance  of  eosinophile  cells  indicates  that  the  lesion  has 
passed  its  acme. 

Bacteriology  of  the  Blood  in  Pneumonia. — That  infection  with 
the  pneumococcus  may  often  take  the  form  of  a  general  blood  infection 
is  indicated  by  the  clinical  course  of  virulent  infections  in  man  and 
animals  and  by  the  frequent  occurrence  of  the  micro-organism  in  the 
blood  of  the  cadaver.  Similar  indications  are  found  in  the  report  by 
Netter  and  Levy  of  finding  the  pneumococcus  in  the  blood  of  a  dead 
fetus  whose  mother  had  died  of  septicemia,  and  by  the  discovery  of  the 
same  germ  in  the  milk  of  a  nursing  woman  who  was  attacked  by  pneu- 
monia.    (Bozolo.) 

Numerous  bacteriological  studies  of  the  blood  during  life  have  shown 
also  that  in  a  moderate  proportion  of  severe  eases  the  pneumococcus 
may  be  obtained  in  culture  by  the  usual  procedure. 


DIPHTHERIA.  255 

Sittmann  obtained  the  largest  proportion  of  positive  results,  6  out  of  16 
cases  examined,  four  of  Avhich  were  fatal  and  gave  signs  during  life  of  gen- 
eral septicemia.  Similar  cases  of  pneumococcus  septicemia  are  reported  hy 
Belfanti,  Netter,  Marchiafava  and  Bignami,Goldscheider,  Grawitz,  Bacciochi, 
and  others,  and  it  has  become  evident  that  in  this  group  of  infections  the 
pneumococcus  is  usuallj'  to  be  found  in  the  blood  during  life.  Other  success- 
ful results  were  obtained  only  a  few  hours  before  death  from  pneumonia,  and 
the  presence  of  the  pneumococcus  in  the  blood  must  be  regarded  as  an  ante- 
mortem  invasion.     (Boulay.) 

Ill  pure  cases  of  lobar  pneumonia,  cultures  made  a  considerable  time 
before  death  have  shown  that  the  pneumococcus  is  rarely  present  in 
the  blood  under  such  circumstances.  Thus  Kraus  and  Kuhnau  ^  had 
only  two  positive  results  in  21  cases,  and  both  were  fatal,  while  most 
of  the  abov^e  writers  have  reported  many  more  negative  than  positive 
results.  Kohn  was  more  fortunate,  finding  the  pneumococcus  in  9  out 
of  32  cases.  Seven  of  the  nine  were  fatal.  James  and  Tuttle  had 
negative  results  in  12  cases,  10  of  which  were  fatal. 

From  these  studies,  it  may  be  concluded  that  when  pneumonia  leads 
to  metastatic  inflammations,  the  pneumococcus  is  frequently  found  in 
the  blood  ;  that  in  some  cases  the  blood  is  invaded  just  before  death  ; 
and  that  in  uncomplicated  pneumonia  the  pneumococcus  is  rarely  found 
in  the  blood  during  the  progress  of  the  lesion  and  that  when  it  is  pres- 
ent, the  disease  is  usually  fatal. 

DIPHTHERIA. 

Red  Cells. — The  concentration  of  the  blood  demonstrated  to  a  slight 
degree  in  pneumonia  is  even  more  distinct  in  the  highly  febrile  stages 
of  diphtheria.  Grawitz  refers  the  tendency  to  a  lymphogogic  action  of 
the  diphtheria  toxin  which  he  has  observed  clinically  and  experimen- 
tally to  cause  an  increase  in  the  specific  gravity  of  the  blood.  Although 
Bouchut  foimd  an  average  of  4.3  million  cells  in  93  cases,  a  distinct  re- 
duction, yet  many  of  his  observations  were  made  late  in  the  disease, 
and  individual  cases  often  showed  slight  polycythemia.  Cuffer  re- 
ported extreme  polycythemia,  7.2-7.8  millions  in  three  cases.  Later 
observers,  especially  Morse  and  Billings,  have  closely  followed  the 
changes  in  the  red  cells,  finding  high  normal  proportions,  5.1-5.6 
millions  during  the  first  week.  In  the  second  week  Morse  found  even 
higher  numbers,  once  6.8  millions,  while  Billings,  although  finding  an 
average  loss  of  half  a  million  cells,  encountered  some  cases  with  distinct 
polycythemia.  With  the  fall  in  temperature  slight  anemia  appears  in 
many  cases,  but  not  in  all.  Bouchut  and  Billings  observed  losses  of  2 
million  cells  in  several  cases. 

Morphological  changes  in  the  red  cells  are  not  marked,  but  when 
anemia  develops  there  is  slight  polychromasia  and  the  usual  deficiency 
of  Hb.  Nucleated  red  cells  were  noted  by  Engel.  The  Hb  is  slightly 
diminished  in  the  average  case,  but  may  be  considerably  reduced  in 
cases  which  have  lost  many  red  cells.  Billings  found  an  average  loss 
of  10  percent  in  patients  not  receiving  antitoxine. 


256  PNEUMONIA.     DIPHTHERIA. 

The  Leucocytes. — The  early  observers,  Bouchut,  Cuffer,  Pee,  Halla, 
Limbeck,  and  Riecler,  fully  established  the  presence  of  leucocytosis  in 
diphtheria,  but  only  Bouchut  attempted  to  deduce  any  rules  gov- 
erning its  occurrence.  He  observed  an  increase  in  all  cases,  usually 
proportionate  to  the  severity  of  the  disease,  but  in  septicemic  cases  the 
increase  was  less  marked  and  the  prognosis  fatal.  In  view  of  the 
recent  observations  of  many  myelocytes  or  an  extreme  proportion  of 
lymphocytes  in  diphtheria,  Bouchut's  statement  that  the  blood  of  diph- 
theria may  be  "  leukemic  "  is  not  far  from  the  truth.  More  detailed 
studies  were  contributed  later  by  Gabritschewsky,  Morse,  Ewing,'' 
Billings,^  Engel,  Schlesinger,  and  File. 

The  leucocytosis  of  diphtheria  resembles  in  most  respects  that  of 
pneumonia.  It  begins  very  early  when  the  disease  develops  suddenly, 
and  reaches  its  highest  point  within  one  or  two  days,  or  begins  more 
slowly  and  increases  steadily  for  several  days,  or  until  death.  It 
probably  begins  earlier  and  reaches  its  acme  sooner  in  more  refractory 
individuals,  with  whom  tiie  prognosis  is  comparatively  good. 

The  writer  observed  two  cases  loithout  leucocytosis  until  the  fourth  and 
sixth  days.  In  one  of  these  the  condition  was  probably  referable  to 
prolonged  toxic  hypoleucocytosis,  and  the  patient  died  later.  Not  in- 
frequently the  white  cells  begin  to  rise  only  after  defervescence,  while 
long  persistent  leucocytosis  is  also  of  rather  common  occurrence.  In 
favorable  cases  the  leucocytes  usually  diminish  steadily  after  the  first 
few  days.  In  fafal  case.'<  the  leucocytes  may  steadily  increase  or  may 
steadily  decrease  during  the  days  before  the  fatal  issue,  or  there  may 
be  no  leucocytosis. 

The  height  of  thp:  leucocytosis  is  usually  considerable,  25,- 
000-30,000  cells  being  frequently  present  in  severe  cases.  The  ma- 
jority of  fatal  cases  at  some  period  show  between  25,000-o0,000  cells, 
hence  the  conclusion  of  Gabritschewsky  that  a  high  and  progressive 
leucocytosis  is  a  bad  prognostic  sign.  Mild  attacks,  especially  in 
adults,  may  not  show  any  increase.  The  writer  found  72,000  cells  in 
one  case  with  lymphocytosis,  while  in  a  peculiar  case  marked  by  hemor- 
rhagic eruption  Felsenthal  counted  148,000 — possibly  an  agonal 
hyperleucocytosis.  The  grade  of  leucocytosis  is  little  affected  by  the 
fever,  but  in  many  cases  is  proportional  to  the  extent  and  depth  of  the 
membrane.  It  may  be  distinctly  affected  by  pneumonia,  but  the 
writer  failed  to  find  any  uniform  lymphocytosis  when  the  cervical 
nodes  were  greatly  enlarged,  nor  did  the  character  of  the  infection, 
whether  pure  or  mixed,  appear  to  influence  the  leucocytes,  (Cf.  File.) 
In  general,  the  leucocytosis  of  diphtheria  is  less  marked  than  that  of 
pneumonia  with  equal  temperature,  and  less  than  that  of  non-diph- 
theritic angina  of  equal  extent.     (File.) 

Types  of  Leucocytes  in  Diphtheria. — With  well-marked  leucocytosis 
the  polynuclear  neutrophile  cells  are  usually  much  increased  in  num- 
bers and  proportions,  but  they  very  seldom  reach  the  very  high  ratios 
seen  in  pneumonia,  probably  on  account  of  the  greater  tendency  of 
children  to  lymphocytosis.     Lympliocytes,  probably  for  the  same  rea- 


EFFECTS  OF  ANTITOXINE  UPON  BLOOD  IN  DIPHTHERIA.       257 

son,  are  relatively  more  abundant.  A  striking  lymphocytosis  occurred 
at  the  height  of  the  disease  in  two  of  the  writer's  cases,  in  one  of  which 
the  lymphocytes,  large  and  small,  formed  60  percent  of  72,000  leu- 
cocytes, and  in  another,  62  percent  of  22,500  cells.  In  neither  was 
there  marked  enlargement  of  cervical  lymph  nodes.  Of  quite  diifer- 
ent  significance  is  the  relative  lymphocytosis  without  increase  in  total 
numbers  which  may  be  seen  in  the  earlier  stages  of  the  disease,  and 
was  noted  by  Billings  in  a  fatal  case  without  leucocytosis,  and  by 
Rieder  and  File  during  convalescence.  Eosinophile  cells  are  usually 
reduced  in  proportion?  ,ften  persist  in  low  normal  ratio,  and  fre- 
quently cannot  be  fon .  at  all.  They  are  relatively  more  numerous 
than  in  pneumonia. 

Engel  made  the  interesting  observation  that  myelocytes,  both  neutro- 
phile  and  eosinophile,  are  frequently  present  in  the  blood  of  diphtheria, 
and  that  when  these  cells  form  over  2  percent,  the  prognosis  is  very 
unfavorable.  In  cases  which  recovered  the  myelocytes  never  formed 
over  1.5  percent,  while  in  7  fatal  cases  they  ran  from  3.6  percent  to 
14.6  percent.  It  should  be  added  that  the  numbers  of  myelocytes 
varied  greatly  from  day  to  day,  and  that  8  of  32  patients  died  with 
few  or  no  myelocytes  in  the  blood. 

Degenerative  changes  in  the  leucocytes  in  diphtheria  are  often  well 
marked.  The  "  leucocyte-shadows  "  of  Klein  are  seen  in  all  severe 
infections  and  may  become  very  numerous  in  fatal  septic  cases.  Even 
before  the  cells  become  fragmented  many  of  them,  principally  the 
poly  nuclear  forms,  show  deficiency  of  chromatin  and  of  neutrophile 
granules.  The  writer,  examining  the  blood  in  .6-percent  salt  solution 
tinged  with  gentian  violet,  found  a  striking  deficiency  of  chromatin  in 
a  case  in  which  the  leucocytosis  disappeared  before  death.  In  the 
other  septic  and  fatal  cases  also  it  was  plainly  apparent,  although  not 
demonstrable  in  less  severe  infections.  This  change  in  the  leucocytes, 
which  may  be  seen  in  other  infectious  diseases,  and  especially  in  acute 
leukemia,  must  be  classed  with  the  general  cellular  degenerations  which 
mark  the  status  infectiosus.  Its  significance  in  diphtheria  has  been 
fully  discussed  by  Gabritschewsky,  while  Fil6  believes  that  these  pale 
staining  cells  are  necrotic.  The  writer  believes  that,  with  careful 
technique,  variations  in  the  staining  capacity  of  leucocytes  may  be 
made  of  value  in  prognosis. 

An  increased  acidophile  tendency  of  the  neutrophile  granules  ap- 
peared to  be  demonstrable  in  some  of  the  writer's  fatal  cases.  Kan- 
thack  has  also  noted  a  similar  change  in  the  staining  tendency  of  the 
pseudo-eosinophile  granules  in  rabbits  which  had  received  small  injec- 
tions of  microbic  poisons. 

Effects  of  Antitoxine  Upon  the  Blood  in  Diphtheria. — The  red 
cells  show  no  distinct  or  uniform  effects  from  the  injections  of  anti- 
toxine, although  in  some  healthy  subjects  there  is  a  moderate  reduction 
lasting  a  few  hours.  On  the  other  hand  the  use  of  antitoxine,  by 
limiting  the  progress  of  the  infection,  tends  to  prevent  further  destruc- 
tion of  blood  cells. 
17 


258  PNEUMONIA.    DIPHTHERIA. 

Within  half  an  hour  after  the  injection  of  antitoxine,  the  leucocytes, 
especially  the  polynuclear  forms,  if  previously  abundant,  show  a 
marked  diminution,  and  in  most  cases,  although  the  leucocytosis 
returns  after  24-48  hours,  it  seldom  reaches  its  previous  grade. 

The  writer  noted  the  reduction  of  leucocytes  after  antitoxine  in  all 
but  two  fatal  cases,  while  Schlesinger  found  it  in  all  of  his  examina- 
tions. It  has  also  been  noted  by  File.  In  the  writer's  cases  the  loss 
was  from  4,000  to  15,000,  but  Schlesinger  observed  a  loss  of  20,000 
within  seven  hours  after  the  injection.  In  some  fatal  cases  the  use  of 
antitoxine  is  followed  immediately  by  distinct  hyperleucocytosis.  (The 
writer,  Gundobin.)  The  most  favorable  cases  show  a  steady  diminu- 
tion of  white  cells  after  the  injection,  but  in  many  fatal  cases  this  re- 
duction is  interrupted  after  the  third  to  fourth  day.  In  critical  cases 
with  many  pale  staining  leucocytes  the  writer  found  an  improvement 
in  the  staining  quality  of  many  polynuclear  cells  shortly  after  the  in- 
jection of  antitoxine.  In  some  fatal  cases  this  change  could  not  be 
detected. 


CHAPTER   XII. 
THE   EXANTHEMATA. 

VARIOLA. 

Red  Cells. — During  the  febrile  period  Hayem  found  very  little 
change  in  the  red  cells,  while  in  the  stage  of  suppuration  polycythemia 
was  sometimes  to  be  noted.  Immediately  after  defervescence,  when 
the  destruction  of  blood  cells  through  the  septic  process  was  no  longer 
masked  by  the  concentrating  influence  of  fever,  the  red  cells  showed  a 
sudden  reduction.  In  a  case  of  confluent  smallpox  there  was  a  loss 
of  2  million  cells.  In  a  fatal  case  before  death  there  were  4.6  million 
cells,  while  in  another,  markedly  hemorrhagic,  there  were  only  2 
millions. 

Pick,  from  his  study  of  42  cases,  found  very  little  change  in  the  red 
cells  throughout  the  entire  course  of  the  disease.  He  failed  to  find 
any  severe  anemia,  although  many  of  his  cases  were  hemorrhagic  and 
confluent.  In  severe  cases  which  recovered  the  red  cells  remained 
normal  before  the  eruption,  almost  invariably  increased  during  the 
suppurative  stage,  even  in  hemorrhagic  cases,  and  after  defervescence 
or  before  death  were  rarely  found  much  below  their  original  figure. 

The  usual  condition  of  the  blood  after  smallpox  appears  to  be,  there- 
fore, a  mild  form  of  chlorotic  anemia,  while  under  some  rather  unusual 
conditions  this  anemia  may  become  severe. 

Leucocytes. — Although  leucocytosis  was  demonstrated  in  the  erup- 
tive stage  of  variola  by  Brouardel,  Hayem,  Halla,  and  Pee,  the  de- 
tailed knowledge  of  the  subject  has  been  contributed  in  a  remarkable 
study  by  R.  Pick. 

Mild  cases  of  varioloid  with  scanty  eruption  ran  their  course,  under 
Pick's  observation,  with  normal  or  subnormal  numbers  of  leucocytes, 
but  when  suppuration  occurred,  the  leucocytes  were  increased,  reaching 
in  one  case  20,000. 

Variola,  also,  even  in  high  febrile  periods  of  the  early  stages  of  the 
most  severe  cases,  failed  to  excite  leucocytosis,  up  to  the  day  of  death, 
showing  that  this  infection  when  uncomplicated  does  not  tend  to  excite  leu- 
cocytosis. Secondary  infection  with  pyogenic  bacteria,  however,  in- 
creased the  leucocytes  after  the  usual  manner,  and  in  nearly  all  of 
Pick's  cases  there  was  well-marked  leucocytosis  beginning  with  the 
appearance  of  the  vesicles,  increasing  as  the  exudate  became  purulent 
and  reaching  its  height  when  suppuration  became  most  active. 

In  cases  which  recovered  the  leucocytes  returned  slowly  to  the  nor- 
mal as  suppuration  subsided.     Abscesses  frequently  interrupted  recov- 


260  THE  EXANTHEMATA. 

ery  and  caused  marked  exacerbations  of  the  leucocytosis.  In  seven  of 
eight  cases  dying  from  pneumonia  there  was  a  rapid  and  steady  de- 
crease of  leucocytes  although  suppuration  continued. 

The  grade  of  leucocytosis  was  usually  proportionate  to  the  severity 
of  the  septic  process. 

Biological  Examinations  of  the  Blood  in  Variola. — In  1887  G.  Pfeiffer 
called  attention  to  the  presence  in  vaccine  lymph  of  small  unicellular  ame- 
boid bodies,  and  the  following  year  he  fouud  these  same  bodies  in  human 
lymph.  These  observations  were  soon  confirmed  by  Rieck  and  later  by 
Ogata,  who  classed  the  bodies  as  Protozoa,  order  Gregarinidee. 

Guarnieri,  in  1892,  believed  that  he  had  cultivated  the  same  bodies  in  the 
epithelial  cells  of  the  rabbit's  cornea,  and  although  Ferroni  and  Massari 
claimed  that  Guarnieri's  parasites  were  degenerating  nuclear  products,  sub- 
sequent observers  have  succeeded  in  verifying  Guarnieri's  conclusions. 

In  1894  Pfeiffer  reported  the  discovery  of  amebse  in  the  blood  of  smallpox 
patients,  describing  them  as  free  in  the  plasma,  about  one -fourth  the  size  of 
red  cells,  possessing  one  or  more  nuclei,  and  projecting  pseudopodia. 

Weber  and  Doehle  have  described  in  the  blood  of  measles,  scarlet  fever, 
and  smallpox,  several  forms  of  ameboid  bodies  which  they  believe  to  be  de-  . 
velopmental  stages  of  a  parasitic  protozoon. 

In  1897  Reed  found  pigmented  ameboid  bodies  in  the  blood  of  vaccinated 
monkeys  and  children,  and  in  the  blood  of  variola,  but  he  found  the  same 
bodies  in  noi-mal  subjects,  and  he  could  not  demonstrate  any  nucleus. 

Kruse,  reviewing  the  evidence  in  1897,  ascribed  great  significance  to  Guar- 
nieri's bodies  in  the  epithelial  cells  of  the  cornea,  believing  that  they  repre- 
sent the  first  stage  in  the  solution  of  the  etiology  of  variola,  but  he  did  not 
grant  equal  importance  to  the  bodies  found  in  the  blood. 

Widal  and  Bezancon  are  reported  to  have  found  streptococci  in  the  blood 
of  six  cases  of  variola. 

VACCINIA. 

Sobotka  examined  the  blood  of  43  children  after  vaccination,  mak- 
ing the  following  observations  : 

The  red  cells  and  Hb  showed  no  constant  variations,  and  usually 
remained  normal. 

Vaccination  always  caused  a  leucocytosis,  beginning  usually  on  the 
third  or  fourth  day  after  inoculation  and  gradually  falling  till  the 
seventh  or  eighth  day  when  the  leucocytes  were  frequently  subnormal. 
From  the  tenth  or  twelfth  day  a  secondary  leucocytosis  regularly  ap- 
peared, lasting  two  to  six  days,  and  showing  close  relation  to  the  ac- 
tivity of  the  virus  and  the  number  of  the  pustules. 

The  height  of  the  first  leucocytosis  varied  between  12,000  and  23,- 
000;  that  of  the  second  between  10,000  and  17,500;  while  in  the 
intermediate  period  the  cells  fell  as  low  as  3,500.  In  uncomplicated 
cases  the  lowest  figures  usually  corresponded  to  the  highest  tempera- 
ture, the  leucocytosis  preceding  by  several  days  the  local  and  general 
manifestations  of  vaccinia. 

VARICELLA. 

Engel  ^  found  67  percent  of  polynuclear  cells,  with  absence  of  eosins, 
in  a  child,  at  the  height  of  the  pustular  stage.     Three  days  later,  when 


SCARLET  FEVER.  261 

most  of  the  pustules  were  healed,  the  polynuclear  cells  had  fallen  to  47 
percent,  and  the  eosins  risen  to  16  percent.  The  total  numbers  of 
leucocytes  were  not  stated,  but  the  above  proportions  indicate  a  mod- 
erate leucocytosis. 

SCARLET    FEVER. 

Hayem  gave  the  first  systematic  account  of  the  blood  changes  in 
scarlatina,  finding  a  loss  of  about  one  million  red  cells  after  deferves- 
cence, and  a  moderate  leucocytosis  in  average  cases,  much  increased  by 
severe  angina  or  by  suppurative  processes.  Somewhat  isolated  obser- 
vations were  reported  by  many  of  the  earlier  blood  analysts,  Halla, 
Pee,  Pick,  Peinert,  Sadler,  while  considerable  series  of  cases  were 
studied  by  Pieder  and  Kotschetkoff. 

The  ichole  blood  suffers  in  a  slight  degree  the  usual  effects  of  fever. 
The  formation  of  fibrin  is  usually  increased  especially  when  there  are 
extensive  angina  or  suppurative  complications.  (Hayem.)  Heubner 
noted  heraoglobinemia  in  one  case,  representing  the  septicemic  type  of 
the  disease. 

Red  Cells. — The  gradual  loss  of  red  cells  noted  by  Hayem  was  fully 
verified  by  Kotschetkoff  who  found  a  reduction  to  3  millions  or  lower 
in  nearly  all  cases.  The  regeneration  of  the  blood  was  slow  and  com- 
plete only  after  6  weeks  or  longer.  On  the  other  hand  Zappert  found 
less  than  4  million  cells  in  only  one  of  six  cases,  and  very  slight  anemia 
was  noted  in  a  considerable  number  of  cases  examined  at  varying 
periods  by  Leichenstern,  Arnheim,  Pee,  Pick,  Reinert,  Sadler,  and 
Felsenthal. 

Leucocytes. — Kotschetkoff  classified  the  leuoocytoses  in  three 
groups,  the  mild  cases,  showing  between  10,000  and  20,000  white  cells, 
the  moderately  severe  cases,  with  20,000-30,000  cells,  and  very  severe 
and  usually  fatal  cases  with  a  leucocytosis  of  30,000-40,000  cells, 
while  in  some  rapidly  fatal  cases  over  40,000  leucocytes  were  found. 
Yet  Rieder's  10  observations  never  gave  more  than  25,000  cells,  and 
usually  less  than  20,000,  although  some  of  his  cases  were  complicated 
with  pneumonia  and  croupous  pharyngitis,  and  were  fatal.  Felsen- 
thal's  6  cases  in  children  were  of  moderate  severity  and  showed  18,- 
000-30,000  cells. 

The  leucocytosis  begins  1—2  days  before  the  appearance  of  the  rash, 
reaches  its  height  with  or  shortly  after  the  full  development  of  the 
eruption,  and  while  in  some  cases  rapidly  falling  with  the  eruption, 
usually  continues  for  4—5  days  longer,  and  very  often  persists  for  days 
or  weeks  after  the  temperature  has  become  normal. 

The  grade  of  leucocytosis  seems  in  general  to  correspond  with  the 
severity  of  the  disease,  especially  of  the  angina,  but  not  with  the  height 
of  the  temperature.  Complications  ^  such  as  lymphadenitis,  otitis, 
nephritis,  usually  have  little  effect  on  the  leucocytes  (Kotschetkoff), 
l)ut  Pee  observed  two  cases  in  which  the  leucocytosis  increased  when 
the  lymph  nodes  began  to  swell  late  in  the  disease.  Pneumonia  caused 
but  slight  increase  in  some  of  Rieder's  cases. 


262  THE  EXANTHEMATA. 

Types  of  Leucocytes. — The  percentage  of  polynuclear  cells  is  in  all 
cases  much  increased,  varying  from  85-98  percent,  according  to  the 
intensity  of  the  disease,  reaching  the  highest  point  on  the  second  day 
of  the  exanthem,  and  thereafter  slowly  declining.  In  fatal  cases  the 
proportion  of  polynuclear  cells  falls  but  slightly,  or  soon  regains  or 
passes  the  original  figure. 

The  eosinophile  cells  may  show  characteristic  variations.  In  all  but 
very  severe  cases  they  are  normal  or  subnormal  at  first,  steadily  increase 
after  2—3  days,  reaching  a  maximum  of  8—15  percent  in  the  second  or 
third  weeks,  and  thereafter  declining  slowly,  reach  the  normal  figure 
about  the  sixth  week.  In  fatal  cases  the  eosins  may  disappear  early  in 
the  disease. 

The  lymphocytes  are  at  first  diminished,  but  later  rise  to  normal  pro- 
portions. 

The  above  rules  deduced  by  Kotschetkoff,  while  probably  represent- 
ing the  average  case,  are  not  always  applicable.  Thus  Weiss  found  no 
eosins  in  one  case  at  the  height  of  the  exanthem.  Rille  observed 
marked  eosinophilia  in  a  fatal  case  ;  Bensaude  observed  as  high  as  20 
percent  of  eosins  in  one  instance  ;  Klein  reports  lymphocytosis  during 
convalescence  ;  and  many  writers  (Rieder,  Turk)  have  described  a  high 
persistent  leucocytosis,  especially  in  those  cases  followed  by  nephritis 
or  other  complications.  Turk  has  called  attention  to  the  remarkable 
change  which  the  leucocytes  undergo  about  the  fifth  day  of  the  disease, 
when  the  polynuclear  cells  rapidly  diminish  and  eosins  and  lympho- 
cytes rapidly  increase.  This  "  secondary  leucocytosis  "  he  likens  to 
the  somewhat  similar  phenomenon  seen  in  variola. 

Bacteriological. — Raskin  found  fitreptococciis  pyogenes  in  the  circu- 
lating blood  in  2  of  64  cases,  while  all  other  culture  was  sterile. 
Negative  results  were  obtained  in  2  cases  by  Sittmann  and  in  4  cases  by 
Kraus. 

MEASLES. 

The  red  cells  have  been  found  in  the  great  majority  of  cases  to  suffer 
little  or  no  change,  but  a  loss  of  Hb  is  usually  demonstrable  after  def- 
ervescence. 

In  adults,  uncomplicated  measles  never  causes  leucocytosis  but  is 
characterized  rather  by  hypoleucocytosis,  reaching  in  one  of  Rieder's 
cases  2,700  cells.  From  4,000  to  6,000  cells  are  commonly  seen. 
This  fact  was  first  noted  by  Pee,  and  has  been  confirmed  by  Pick, 
Rieder,  Rille,  Felsenthal,  and  others. 

Normal  or  slightly  reduced  numbers  of  white  cells  are  found  at  the 
onset  of  the  disease.  At  the  height  of  the  exanthem  they  are  usually 
at  their  lowest  figure  (Pee,  Turk),  and  return  to  the  normal  within  a 
few  days  or  a  week  after  defervescence.  When  the  bronchitis  is  severe 
there  may  be  a  moderate  leucocj^tosis,  Hayem  finding  10,000-14,000 
cells  in  such  cases  occurring  in  children.  Rieder  observed  slight  leu- 
cocytosis in  a  case  complicated  by  catarrhal  pneumonia.  Cabot  ob- 
served 9,000  cells  in  two  cases,  one  hemorrhagic.     The  writer  found 


GERMAN  MEASLES.  263 

no  leucocytosis  in  three  cases  occurring  in  malarious  subjects.     The 
malarial  parasites  reappeared,  with  chills,  during  convalescence. 

The  proportions  of  the  various  leucocytes  show  no  distinctly  ab- 
normal variations.  Turk  found  a  rather  high  percentage  of  poly- 
nuclear  cells  during  the  fever,  with  diminution  of  small  lymphocytes. 
Pee,  Klein,  and  Turk  noted  an  excess  of  large  mononuclear  cells. 
The  eosins  are  usually  in  low  normal  proportions  during  the  early  fe- 
brile period,  but  tend  to  diminish  as  the  eruption  declines.  Yet  Turk 
found  nearly  5  percent  during  the  second  week  of  the  disease. 

Bacteriological  examination  of  the  blood  was  negative  in 
10  cases  examined  by  Barbier.  Weber  claims  to  have  found  in  the 
blood  of  measles  a  protozoon,  which  he  has  also  seen  in  variola. 

Applications  in  Diagnosis. — Typical  cases  of  measles  and  scarlet 
fever  may  sometimes  be  distinguished  from  each  other  in  their  early 
stages  by  the  examination  of  the  blood.  Yet  as  Turk  says,  the  blood 
in  measles  strongly  resembles  that  of  a  mild  scarlatina,  as  both  show  a 
nearly  normal  number  of  leucocytes  and  normal  proportions  of  eosins. 
Yet  equally  severe  constitutional  disturbance  should  give,  on  the  second 
to  third  days,  leucocytosis,  if  scarlatinal,  normal  or  diminished  leucocytes, 
if  from  measles. 

In  German  measles  there  was  no  leucocytosis  in  2  cases  men- 
tioned by  Cabot. 


CHAPTER   XIII. 
TYPHOID   FEVER. 

The  whole  blood  commonly  sufiers  concentration  in  the  early 
stages  of  the  disease  as  a  result  of  the  febrile  process,  while  at  any 
period  profuse  diarrhea  and  repeated  hemorrhages  considerably  reduce 
the  total  bulk.  This  concentration  is  so  marked  and  constant  that  the 
deep  red  appearance  of  the  blood  drop  in  typhoid  fever  is  a  very  char- 
acteristic differential  sign  between  this  disease  and  pernicious  malaria. 

Fibrin  formation  is  usually  deficient  and  may  not  be  demonstrable 
at  all,  but  with  inflammatory  complications  this  element  may  reappear 
and  become  abundant.     (Hayem,  Turk.) 

Red  Cells. — During  the  febrile  period  the  red  cells  usually  show  a 
slight  and  gradual  decline.  Yet  the  initial  concentration  of  the  blood 
often  yields  moderate  polycythemia  during  the  first  two  weeks  or 
longer,  so  that  the  slight  anemia  is  not  to  be  noticed  till  the  fever  and 
diarrhea  subside.  (Sadler,  Felsenthal,  Thayer.)  Even  when  distinct 
polycythemia  does  not  result  the  same  factors  tend  to  keep  up  the  pro- 
portion of  red  cells,  so  that  in  the  vast  majority  of  cases  of  typhoid 
fever  the  red  cells  fall  within  normal  limits,  and  the  presence  of  slight 
anemia  can  be  demonstrated  only  by  following  the  case  from  the  first. 
Accordingly,  nearly  all  observers  have  reported  over  4  million  red 
cells,  and  many  over  5  millions  during  the  febrile  period. 

The  Hb  suffers  to  a  greater  extent,  and  in  spite  of  the  concentra- 
tion of  the  blood  most  febrile  cases  register  between  70  and  80  per- 
cent of  Hb.  Severe  diarrhea  ©r  long  hemorrhages  may  at  any  time 
cause  marked  oscillations  in  the  red  cells  and  Hb.  After,  and  often 
before  defervescence,  the  blood  may  show  distinct  anemia,  which  with 
rapid  defervescence  may  appear  suddenly.  (Arnheim,  Zaslein,  Boeck- 
man,  Laache.)  During  convalescence  the  anemia  slowly  disappears, 
the  Hb  being;  restored  much  later  than  the  red  cells. 

The  grade  of  anemia  observed  after  typhoid  fever  varies  greatly  with 
the  character  of  the  disease.  Uncomplicated  cases  may  show  no  dis- 
tinct reduction  of  cells  and  very  slight  loss  of  Hb.  In  a  considerable 
proportion  of  severe  cases  the  red  cells  fall  below  4  millions  and  the 
Hb  below  70  percent.  Kohler  in  29  cases  found  an  average  loss  of 
19.4  percent  of  Hb  in  men,  and  20.4  percent  in  women,  while  the 
average  of  red  cells  for  men  was  4.03  millions,  and  for  women  3.58 
millions.  Hayem,  Thayer,  Henry,  and  others  have  reported  severe 
grades  of  pernicious  anemia  as  sequelae  of  typhoid  fever.  In  one  of 
Henry's  cases  there  were  only  804,000  red  cells. 

Morphological  changes  are  usually  not  marked,  but  in  severe 


LEUCOCYTES.  265 

cases  Turk  found  megalocytes,  small  microcytes,  and  polychromasia,  in 
comparative  abundance.  Nucleated  red  cells  may  appear  after  hem- 
orrhage. 

Leucocytes.  Numbers. — In  the  first  week  uncomplicated  cases 
nearly  always  show  a  normal  number  of  leucocytes,  but  severe  angina, 
bronchitis,  enteritis,  etc.,  may  yield  a  moderate  polynuclear  leucocy- 
tosis.  Klein  and  Aporti  regarded  this  initial  leucocytosis  as  of  fre- 
quent occurrence,  but  most  other  observers  have  failed  to  encounter  it. 
The  writer  has  seen  some  examples. 

In  the  second  week  the  leucocytes  usually  show  a  distinct  reduction, 
especially  of  the  polynuclear  forms,  but  the  number  of  leucocytes  found 
at  this  time  is  by  no  means  constant. 

In  some  cases  the  lowest  figures  of  the  disease  are  reached  in  the 
second  week  (Turk,  Chetagurow),  while  in  others  there  is  no  distinct 
reduction  at  this  time  (v.  Jaksch,^  Sadler). 

In  the  third  and  fourth  weeks  the  leucocytes  usually  continue  to 
diminish  until  the  acme  of  the  disease  is  reached  (Turk),  after  which 
they  slowly  increase.  In  many  cases  the  lowest  figures  are  reached  at 
this  period  (Rieder,  Turk,  Thayer),  but  sometimes  the  reduction  con- 
tinues till  after  defervescence  (Klein). 

A  relation  between  the  leucocytes  and  the  fever  seldom  exists  nor 
does  the  size  of  the  spleen  appear  to  influence  the  number  or  type  of 
the  leucocytes.  (Turk.)  That  the  reduction  of  the  white  cells  is  de- 
pendent on  the  action  of  the  typhoid  toxine  is  indicated  by  the  further 
losses  which  commonly  go  with  unfavorable  turns  in  the  disease. 
(Rieder,  Jez,  Turk,  Nagaeli.)  It  is  thei^ejore  a  general  rule  that  the 
more  severe  the  typhoid  intoxication  the  lower  is  the  count  of  leucocytes. 
The  reduction  is  seldom  below  2,000  cells,  but  1,000-2,000  were 
reported  by  Hayem,  Limbeck  and  Rieder,  Cabot,  and  Kohler.  In 
Thayer's  cases  the  lowest  weekly  average  was  5,877,  and  was  obtained 
in  the  fourth  week,  but  the  majority  of  cases  at  some  periods  show  be- 
tween 4,000  and  6,000  cells,  and  many  fall  below  4,000. 

Leucocytosis  during  the  course  of  typhoid  fever  is  by  no  means 
uncommon.  Usually  a  severe  diarrhea  from  extensive  ulcers,  or  hem- 
orrhage, or  pneumenia,  or  other  exudative  or  suppurative  complica- 
tions, may  be  found  to  explain  the  increase.  Yet  several  reported 
cases  with  leucocytosis  have  shown  no  such  complications  (Aporti), 
and  a  short  experience  at  the  bedside  seldom  fails  to  bring  to  light 
some  moderate  leucocytoses  without  apparent  cause.  On  the  other 
hand  leucocytosis  may  fail  in  the  presence  of  pneumonia  or  other 
markedly  exudative  complications.  (Turk,  the  writer,  Cabot.)  Kohler 
found  6,200  and  4,200  leucocytes  in  cases  complicated  by  severe 
bronchitis.  After  hemorrhage  in  one  case  the  white  cells  remained 
at  2,600,  in  tM^o  others  there  was  an  increase  of  about  4,000  cells. 
Complicating  pneumonia  once  reduced  the  leucocytes  from  2,600  to 
1,000,  at  another  time  they  remained  at  6,300,  and  twice  11,200  and 
11,800  cells  were  counted.     (Kohler.) 

Cold  baths  have  long  been  known  to  cause  temporary  massing  of 


266  TYPHOID   FEVER. 

leucocytes  in  peripheral  capillaries.  (Winternitz.)  lu  20  cases  Thayer  ^ 
found  an  average  increase  of  5,346  cells,  and  a  maximum  increase  of 
17  000.  With  the  return  of  peripheral  circulation  the  excess  of  cells 
disappears. 

Perforation  usually  causes  poly  nuclear  leucocytosis  but  there  may  be 
no  effect  upon  the  leucocytes,  or  the  percentage  of  polynuclear  cells 
may  rise  without  increase  in  their  total  number. 

Types  of  Leucocytes. — Daring  the  first  week  of  the  disease  the  per- 
sistence of  a  normal  proportion  of  lymphocytes  without  increase  of  neu- 
trophile  cells  is  a  very  characteristic  feature  of  typhoid  blood.  Bar- 
ring the  occasional  occurrence  of  initial  polynuclear  leucocytosis,  from 
the  end  of  the  first  week  there  is  a  progressive  increase  of  the  lympho- 
cytes and  diminution  of  the  neutrophile  cells.  At  first  the  lympho- 
cytes do  not  pass  beyond  high  normal  limits,  but  during  the  third, 
fourth,  and  fifth  weeks,  or  later,  they  usually  occur  in  distinct  excess. 
While  mononuclear  cells  seldom  fall  below  30  percent  at  any  stage  of 
the  disease  a  proportion  of  40-60  percent  is  then  seen.  Among  these 
cells  the  proportion  of  small  lymphocytes  is  often  striking.  In  some 
cases  there  is  a  very  marked  absolute  lymphocytosis.  In  one  of  the 
writer's  cases  at  Montauk,  the  blood  resembled  that  of  lymphatic  leu- 
kemia, a  resemblance  rendered  still  more  striking  by  the  enormous  size  of 
the  mesenteric  nodes  at  autopsy.  With  the  increase  of  mononuclear 
cells  the  numbers  of  polynuclear  cells  gradually  fall,  reaching  50  percent 
in  most  cases  and  occasionally  a  much  lower  figure.  (35  percent,  Jez  ; 
20  percent,  Klein.)  The  excess  of  lymphocytes  usually  persists  during 
the  first  weeks  of  convalescence  and  may  not  reach  its  acme  until  this 
time,  while  Ouskow  found  that  normal  relations  were  not  restored  till 
the  tenth  or  eleventh  week.  Nagaeli  describes  the  development  during 
convalescence,  especially  in  children,  of  a  well-marked  lymphocytosis 
with  a  moderate  increase  of  neutrophile  cells.  In  children  this  lym- 
phocytosis was  most  marked  2—3  months  after  the  fever,  while  in  adults 
it  was  less  marked  and  disappeared  by  the  end  of  the  second  month. 

Eosins  are  usually  absent  or  very  scarce  during  the  febrile  period, 
but  reappear  shortly  before  (Nagaeli),  during,  or  after  defervescence. 
Aporti  found  as  high  as  18  percent  during  the  intermittent  pyrexia  at 
the  end  of  the  disease,  but  they  are  usually  much  less  abundant. 

Degenerative  changes  in  the  leucocytes  occur  as  usual,  Jez  reporting 
large  numbers  of  pale  leucocyte-shadows  in  severe  cases.  Glycogen 
was  found  in  the  leucocytes  in  increased  quantity  between  the  twelfth 
and  twentieth  days  by  Livierato. 

Applications  in  Diagnosis. — The  morphological  examination  of  the 
blood  is  often  of  great  assistance  in  the  diagnosis  of  typhoid  fever  and 
the  diseases  which  simulate  it.  The  writer  knows  of  no  clearer  illus- 
tration of  this  fact  than  those  which  he  reported'  in  1893,  and  which 
have  been  paralleled  from  numerous  later  observations  and  by  many 
writers  both  before  and  since. 

Suppurative  processes,  if  active,  may  usually  but  not  always,  be  dis- 
tinguished from  typhoid  fever  by  the  presence  of  polynuclear  leucocy- 


BACTERIOLOGICAL.  267 

tosis.  Yet  it  shpuld  be  remembered  that  slow  suppuration,  or  the 
mere  presence  of  pus  the  secretion  of  which  has  ceased,  are  frequently 
unaccompanied  by  leucocy tosis  or  are  even  marked  by  relative  lym- 
phocytosis. Thus  the  writer  found  50  percent  of  lymphocytes  among 
11,000  cells  in  a  case  of  large  abscess  of  the  liver  with  mild  typhoidal 
symptoms,  and  45  percent  of  lymphocytes  among  7,000  cells  with  the 
chest  full  of  pus.  With  increasing  experience  therefore,  the  writer 
believes  that  most  careful  observers  will  recognize  the  partial  justice 
of  Grawitz's  claim  that  in  difficult  cases  the  blood  examination  here 
often  fails  to  be  of  service. 

Among  the  conditions  which,  by  the  almost  invariable  presence  of 
leucocytosis,  may  be  distinguished  from  typhoid  fever,  are  bacterial  en- 
docarditis, suppurative  appendicitis,  and  pneumonia.  Malaria  of  suf- 
ficient gravity  to  simulate  typhoid  fever  can  nearly  always  be  distin- 
guished by  the  anemic  appearance  of  the  blood  drop  as  compared  with 
the  deep  red  concentrated  blood  of  typhoid  fever.  An  astonishing 
change  in  the  blood  was  often  noted  at  Montauk  when  typhoid  fever 
developed  in  subjects  of  malarial  cachexia,  and  in  no  instance  were 
malarial  parasites  found  in  such  concentrated  blood.  In  acute  par- 
oxysms the  discovery  of  the  parasite  is  usually  possible,  but  chronic 
malaria  without  parasites  in  the  blood  may  simulate  typhoid  fever. 

Bstween  miliary  tuberculosis,  typhoid  fever,  and  some  forms  of 
meningitis,  Widal's  test  is  required  and  the  enumeration  of  leucocytes 
is  of  little  value. 

From  an  extensive  study  of  the  leucocytes  in  typhoid  fever  Nagaeli 
draws  the  following  conclusions  regarding  jjrognosls.  The  prognosis 
is  favorable :  (1)  When  eosins  are  present  at  the  height  of  the  disease,  or 
reappear  in  the  second  or  third  stages  of  the  febrile  period.  (2)  When 
lymphocytes  begin  to  increase  after  the  severest  toxemia  is  past.  (3) 
The  diminution  of  neutrophile  cells  is  slight  only  in  more  favorable 
cases.  Unfavorable  signs  are  :  (1)  Very  small  numbers  of  all  varieties 
of  leucocytes.     (2)  Failure  of  leucocytosis  with  complications. 

Bacteriolog"ical. — In  the  hope  of  developing  a  method  of  early 
diagnosis  of  typhoid  fever  many  biological  studies  of  the  blood  have 
been  undertaken.  Aspiration  of  the  spleen  has  given  successful  results 
in  the  majority  of  cases  (Chantemesse  and  Widal,  Redtenbacher,  Lu- 
catello,  Neisser,  Bruschettini),  but  this  dangerous  procedure  cannot  be 
generally  adopted.  Yet  the  results  of  Silvestrini  who  found  the  typhoid 
bacillus  in  the  aspirated  blood  of  the  spleen  in  four  cases  in  which  there 
were  no  characteristic  intestinal  lesions  are  most  suggestive. 

In  blood  drawn  from  the  skin  or  rose  sjjots,  negative  results  were  ob- 
tained by  Chantemesse,  Widal,  Janowski,  Merkel,  Seitz,  Lucatello, 
Urban,  and  small  proportions  of  positive  results  have  been  secured  by 
Rutimeyer,  Wiltschour,  Frankel,  Grawitz,  Menas,  and  jNIenzer.  About 
50  percent  of  successful  tests  were  made  by  Sudakoff  and  Thiemich, 
while  Neuhaus^  has  recently  succeeded  in  cultivating  the  typhoid 
bacillus  from  the  rose  spots  in  13  of  14  cases. 

In  the  circulating  blood  during  life  the  typhoid  bacillus  has  been  ob- 


268  TYPHOID  FEVER. 

tained  in  one  case  each  by  Pasquale,  Thiemich,  Bloch,  and  Kraus,  and 
twice  by  Ettlinger  and  by  Stern.  Kuhnau  secured  1 1  positive  cultures 
n  41  cases,  examining  blood  drawn  from  the  basilic  vein,  at  the  acme 
of  the  disease.  Of  38  cases  examined  by  James  and  Tuttle  there  were 
3  positive  results,  one  only  proving  fatal. 

On  the  other  hand,  entirely  negative  results  in  about  40  cases  are  re- 
ported by  Neuhaus,  Ettlinger,  Frankel,  Klein,  Bloch,  and  by  many 
others. 

That  the  disease  may  assume  the  character  of  a  mixed  septicemia  is 
indicated  by  a  considerable  number  of  reports  of  the  presence  in  the 
blood  of  other  bacteria,  especially  Staphylococcus  aureus.  (Loisson,  Sitt- 
mann,  Kraus.) 

From  the  above  synopsis  of  the  work  in  this  field,  it  appears  that 
bacteriological  blood-analysis  in  typhoid  fever  can  have  only  a  very 
limited  clinical  application.  "While  the  results  obtained  from  the  aspi- 
rated blood  of  the  spleen  are  usually  successful,  and  Silvestrini's  re- 
port of  finding  the  Bacillus  typhosus  in  the  spleen  when  characteristic 
intestinal  lesions  were  absent  is  very  suggestive,  yet  this  procedure  is 
too  dangerous  for  general  use. 

In  the  examination  of  the  blood  drawn  from  the  rose  spots  negative 
results  thus  far  outnumber  the  positive,  although  Neuhaus'  recent  re- 
port is  encouraging.  Kuhnau's  rather  numerous  successful  cultures 
from  considerable  quantities  of  the  circulating  blood  are  the  most 
favorable  yet  recorded. 

While  not  widely  applicable  in  diagnosis  the  bacteriological  ex- 
amination of  the  blood  has,  however,  greatly  extended  our  knowledge 
of  the  morbid  processes  concerned  in  typhoid  fever. 

Bibliography. 

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Albu.     Virchow's  Archiv,  Bd.  149,  p.  405. 
Aporti.     XI.  Internat.  Cong.,  Rome,  III.,  p.  381. 
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270  TYPHOID  FEVER. 

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CHAPTER   XIV. 
WIDAL'S  TEST. 

The  history  of  the  development  of  Widal's  test  from  the  discovery 
of  the  phenomenon  of  Pfeitfer  in  1894  through  its  first  application  to 
the  diagnosis  of  typhoid  fever  by  Pfeiffer  and  Kolle,  and  Gruber  and 
Durham,  in  1896,  up  to  its  more  practical  modification  by  Widal,  has 
now  been  very  fully  reviewed  in  numerous  monographs  and  treatises 
on  bacteriology  and  need  not  here  be  repeated.  It  may  only  be  said 
that  while  the  scientific  basis  of  the  test  had  been  firmly  laid  by 
previous  studies,  up  to  the  time  of  Widal's  communication  there  had 
been  no  indication  that  the  specific  reaction  could  be  obtained  from 
small  quantities  of  serum  and  at  the  beginning  of  the  disease,  while 
the  use  of  dried  blood  and  the  introduction  of  the  test  into  municipal 
laboratories,  thus  rendered  possible,  was  first  accomplished  by  John- 
ston of  Montreal. 

Description  of  the  Reaction, — When  to  a  few  cubic  centimeters  of 
blood  serum  of  a  patient  suffering  from  typhoid  fever  is  added  a  few 
drops  of  an  actively  motile  culture  of  Bacillus  typhosus,  the  bacteria 
are  precipitated  in  flakes,  leaving  the  supernatant  fluid  clear.  When 
the  sediment  is  examined  microscopically  it  is  found  that  the  bacilli 
have  lost  their  motility  and  are  agglutinated  in  masses,  while  with 
very  intense  reactions  they  may  be  broken  up  into  granules  or  even 
completely  dissolved.  When  the  test  is  performed  with  a  drop  of  dis- 
solved blood  inoculated  by  means  of  a  platinum  loop  with  a  small  por- 
tion of  broth  culture,  all  stages  of  the  reaction  may  be  followed  under 
the  microscope. 

With  very  intense  reactions  the  agglutination  is  found  to  be  complete 
as  soon  as  a  cover-glass  can  be  adjusted  over  the  drop  and  the  specimen 
placed  under  focus.  The  bacilli  are  motionless,  they  are  nearly  all 
gathered  in  characteristic  clumps,  which  stretch  in  a  network  irregu- 
larly through  the  field,  and  very  soon,  in  some  cases,  evidences  of  sub- 
division or  solution  of  the  bacteria  may  be  detected. 

If  the  7'eacfion  is  less  complete,  the  clumps  are  less  compact  and  a  few 
motile  bacilli  may  be  found  between  the  masses.  With  high  dilutions 
of  the  blood,  all  stages  of  the  reaction  may  be  followed.  The  first 
change  noted  is  a  partial  loss  of  motility.  The  bacilli  cling  to  one 
another  after  struggling  to  free  themselves,  but  gradually  entangling 
their  neighbors.  In  the  course  of  ten  or  fifteen  minutes  the  process 
results  in  the  gradual  clumping  of  all  bacilli,  or,  according  to  the 
strength  of  the  reaction,  a  variable  number  of  actively  motile  bacilli 
may  remain  between  the  loose  masses. 


272  WIDAL'S  TEST. 

When  the  reaction  is  present  in  traces  only,  much  longer  time  is  re- 
quired for  the  appearance  of  small  clumps,  but  these  reactions  must  be 
discarded  as  unreliable.  All  experienced  observers  have  insisted  that 
distinct  islands  of  clumped  bacilli  must  be  present  to  constitute  a  posi- 
tive reaction,  and  Fischer  and  others  maintain  that  all  bacilli  must  be 
rendered  quiescent  before  the  result  can  be  regarded  as  'positive. 

PsEUDO-REACTioxs. — While  partial  reactions  occur  under  many 
conditions  when  the  technique  has  been  faultless,  certain  eflPects  simu- 
lating the  true  agglutination  may  appear  in  specimens  containing  not 
a  trace  of  the  specific  principle  on  which  the  test  depends.  In  old 
cultures  many  loose  clumps  of  bacteria  may  be  transferred  by  the  loop 
from  the  culture  tube  and  be  mistaken  for  an  effect  produced  by  the 
serum.  Normal  blood  or  serum,  in  somewhat  concentrated  form,  exerts 
a  marked  influence  upon  the  motile  typhoid  bacillus,  causing  it  to  lose 
its  motility  after  a  time,  but  failing  to  develop  typical  clumps.  If  the 
specimen  has  been  allowed  to  dry  many  bacteria  adhere  to  slide  or  cover- 
glass  or  gather  at  the  thickening  edges  of  the  specimen  and  sometimes 
these  collect  in  motionless  groups.  Such  clumps  always  lack  the  re- 
ticular arrangement  seen  in  the  true  reaction.  A  considerable  variety 
of  confusing  appearances  will  meet  the  beginner,  resulting  from  the 
formation  of  fibrin  and  the  incomplete  solution  of  masses  of  red  cells. 

Technics  :  Methods  of  Obtaining  the  Body-Fluid. — Although  specific 
reactions  have  been  obtained  from  many  secretions,  excretions,  and 
other  fluids  of  the  body,  only  the  blood,  its  serum  expressed  from  the 
clot,  or  the  fluid  gathering  in  blisters,  yield  sufficiently  constant  results 
to  be  available  in  clinical  diagnosis. 

The  Whole  Blood. — When  the  examiner  can  reach  the  bedside 
there  is  no  better  method  than  to  employ  the  whole  blood  diluted  ia 
known  proportion  by  distilled  water.  In  order  to  obtain  an  accurate 
dilution  a  medicine  dropper  may  be  graduated  in  one  and  ten  or  twenty 
drop  marks,  as  suggested  by  Cabot,  but  such  dilution  cannot  be  very 
accurate.  The  writer  has  long  used  for  this  purpose  the  leucocyte 
pipette  of  the  Thoma-Zeiss  heraatocytometer,  which  gives  an  exact 
dilution  of  1-20,  or  1-50,  or  more,  and  which  is  itself  a  very  conve- 
nient instrument  for  handling  the  blood.  Levy  and  many  others  have 
devised  special  tubes  adapted  to  this  purpose.  The  chief  objection  to 
this  method  is  the  failure  of  the  blood  to  completely  dissolve  in  dilu- 
tion of  1-20,  or  1-50,  of  water,  but  no  other  method  can  furnish  more 
exact  dilution,  which  is  essential  in  accurate  work.  This  difficulty 
may  be  avoided  by  laying  the  pipette  on  the  side  until  the  corpuscles 
settle. 

Blood  dried  on  a  glass  slide  and  dissolved  by  mixing  with  water  is 
now  used  in  probably  90  percent  of  all  examinations.  One  or  two 
drops  are  touched  to  a  clean  glass  slide  and  dried  in  the  air.  Such  a 
specimen  protected  from  moisture  may  be  kept  for  days,  transported 
for  long  distances,  and  being  easily  obtained,  even  by  the  patient  him- 
self, furnishes  by  far  the  most  practical  method  of  obtaining  the  neces- 
sary material  for  the  test.     Its  great  disadvantage  is  the  impossibility 


DESCRIPTION  OF  THE  REACTION.  273 

of  securing  an  exact  dilution  of  the  blood  when  it  is  redissolved.  This 
difficulty,  while  theoretically  insurmountable,  proves  to  be  of  compara- 
tively little  moment  in  practice,  since  an  experienced  worker  can  learn 
to  control  the  dilution  by  the  color  of  the  drop.  Also,  when  imper- 
fectly dissolved  the  detritus  of  red  cells  may  obscure  the  field,  although 
it  should  not  fail  to  be  distinguished  from  masses  of  bacilli. 

Some  observers  have  found  less  powerful  and  constant  effects  from 
dried  blood  than  from  serum  (Widal,  Delepine,  Johnston),  but  for 
diagnostic  purposes  Park  finds  the  two  methods  of  nearly  equal  value. 
Nevertheless,  for  accurate  studies  of  variations  in  the  reaction,  the  use 
of  dried  blood  is  inapplicable,  although  it  will  probably  always  remain 
in  extensive  employment  for  simple  diagnostic  purposes. 

Serum.  1.  The  Bulbed  Tube. — A  capillary  tube  with  central  bulb 
is  filled  by  capillary  attraction  from  the  expressed  drop,  the  ends  are 
fused,  and  when  the  blood  coagulates  a  few  drops  of  serum  are  exuded. 
A  great  many  modifications  suited  to  individual  purposes  have  been 
suggested  for  this  method.  It  offers  considerable  technical  difficulties, 
but  furnishes  serum  without  delay. 

2.  The  Blister. — Serum  may  be  obtained  by  means  of  a  Spanish  fly 
blister  in  from  6-18  hours  and  in  quantity  sufficient  for  extended  ex- 
amination, without  involving  much  pain  or  inconvenience.  The  fluid 
may  be  drawn  in  a  sterile  test-tube  and  afterwards  divided  in  meas- 
ured quantities,  or  it  may  be  sealed  in  a  capillary  tube.  For  detailed 
study  blister-serum  is  superior  to  all  other  fluids.  For  measuring 
serum  the  *' mixer"  of  the  hematocytometer  is  well  adapted,  and  the 
test  may  be  performed  in  the  hanging  drop  or  in  the  test-tube. 

The  Culture. — Considerable  difference  in  the  response  of  different 
cultures  of  bacilli  have  been  demonstrated  by  Kolle,  Achard  and  Ben- 
saude,  Durham,  v.  de  Velde,  and  Ziemke.  Although  Foerster  found 
very  little  difference  in  a  considerable  series  of  cultures,  most  ob- 
servers agree  that  attenuated  cultures  are  more  often  agglutinated  by 
normal  serum  in  considerable  dilution  (1-10  ;  1-15).  It  appears  that 
for  each  culture  there  is  a  limit  beyond  which  normal  serum  is  posi- 
tively inert,  while  at  the  same  dilution  typhoid  serum  exerts  a  specific 
action.  (Foerster.)  While  any  pure  culture  may  be  used,  the  best 
results  have  been  obtained  in  New  York  City  by  a  so-called  "  Pfeiffer 
specimen"  imported  by  Park.  A  stock  culture  of  this  particular 
growth  is  kept  in  sealed  tubes  of  nutrient  agar  in  the  ice  chest  and  re- 
planted every  few  months.  From  this  growth  the  specimen  employed 
in  testing  is  obtained  in  broth  culture  grown  for  24  hours  at  a  temper- 
ature of  35°  C.  In  such  broth  cultures  the  bacilli  are  completely  iso- 
lated and  actively  motile,  so  that  the  slightest  change  in  motility  or 
tendency  to  clump  can  be  detected  by  comparison  with  a  control 
specimen. 

Dead  Bacilli. — Widal  first  observed   that  cultures   of  typhosus 

which  had  been  killed  by  heat  (57-60°  C,  30-45  minutes)  had  lost 

little  or  none  of  their  capacity  to  agglutinate,  and  this  fact  has  been 

abundantly  attested  by  others.     Many  have  therefore  preferred  to  use 

18 


274  WIDAL'S  TEST. 

a  dead  culture  killed  by  heat,  or  by  10-percent  formalin,  or  by  thymol, 
or  by  corrosive  sublimate  1,000-5,000  (Park),  thereby  dispensing 
with  the  trouble  of  preparing  a  fresh  culture.  Such  an  expedient, 
however,  can  hardly  meet  with  general  adoption,  on  account  of  the 
difficulty  of  keeping  the  dead  bacilli  well  isolated,  and  because  the 
gradual  loss  of  motility  is  a  desirable  and  reassuring  feature  of  the  test 
in  mild  reactions,  which  are  just  the  ones  in  which  uncertain  clinical 
signs  render  a  positive  test  most  desirable. 

Attenuated  cultures  have  been  recommended  by  Johnston,  who 
found  that  in  using  dried  blood  pseudo-reactions  were  not  infrequent 
with  active  virulent  cultures,  while  broth  cultures  planted  from  old 
agar  stock  were  less  susceptible  and  did  not  respond  to  healthy  or  non- 
typhoid  sera.  Others  have  failed  to  find  this  advantage  in  attenuated 
cultures,  which  have  not  come  into  prominent  use  with  either  dry  blood 
or  serum. 

Degree  of  Dilution  of  Serum  and  Time  Required. — Although  it  has 
been  believed  that  the  serum  reaction  in  typhoid  fever  depends  on  the 
presence  in  the  blood  of  a  peculiar  substance  which  exerts  a  specific 
action  on  the  typhoid  bacillus,  yet  it  has  been  found  that  in  a  consider- 
able proportion  of  cases  healthy  serum,  or  that  of  patients  suffering 
from  other  diseases,  contains  substances  which  exert  a  very  similar  in- 
fluence upon  typhoid  cultures.  In  typhoid  fever,  however,  the  sei'uin 
may  usually  be  diluted  20  to  50  times,  or  often  very  much  furthen-  {1,000- 
2,000,  Widal  ^)  without  destroying  the  reaction,  while  in  other  diseases  the 
reactions  usually  disappear  with  dilutions  of  1—10,  or  almost  certainly 
with  dilutions  of  1—20. 

The  element  of  time  is  also  of  great  importance  in  distinguishing  the 
specific  typhoid  reaction  from  that  produced  by  other  sera.  While  a 
distinct  reaction  often  occurs  instantly  with  typhoid  serum,  blood  of 
other  diseases  almost  never  acts  immediately  but  requires  one-half  to 
one  hour  or  longer  to  disclose  its  effects. 

Consequently,  in  order  to  demonstrate  the  specific  typhoid  reaction 
it  is  necessary  to  increase  the  dilution  and  to  limit  the  time. 

"  The  results  obtained  in  the  New  York  City  Health  Department 
laboratories,  and  elsewhere,  have  shown  that  in  a  certain  proportion  of 
cases  not  typhoidal,  there  occurs  a  delayed  moderate  reaction  in  a  1-10 
dilution  of  serum  or  blood ;  but  very  rarely,  if  ever,  excepting  in  ty- 
phoid fever,  does  a  complete  reaction  with  this  dilution  occur  within 
five  minutes.  When  dried  blood  is  used,  the  slight  tendency  of  non- 
typhoid  blood  in  1-10  dilution  to  produce  agglutination  is  increased  by 
the  presence  of  fibrinous  clumps  and  perhaps  by  other  substances  de- 
rived from  disintegrating  red  cells.  From  many  cases  examined  by 
Fraenkel,  Stein,  Foerster,  Scholtz,  ourselves,  and  others,  it  has  been 
found  that  in  dilution  of  1—20  or  more,  a  decided  quick  reaction  is  never 
produced  by  any  febrile  disease  other  than  typhoid  infection,  in  which  it 
often  occurs  in  dilution  of  1—50^     (Park.) 

Yet  even  this  dilution  appears  insufficient  to  eliminate  all  sources  of 
error,  and  there  has    been  a  constant    tendency  among  experienced 


OCCURRENCE  OF  THE  REACTION.  275 

workers  to  increase  the  grade  of  dilution.  Grunbaura  placed  it  at 
1—30  ;  Simon,  at  1—30  or  more  ;  Stern,  after  a  large  experience,  at 
1-40  ;  and  Mewius,  at  1-60. 

From  these  authoritative  opinions  it  becomes  necessary  to  prescribe 
a  dilution  of  at  least  1-20,  better  1-30,  while  the  limit  of  time  should 
not  be  greatly  extended.  Even  these  limits  will  be  found  insufficient 
to  avoid  all  possible  error,  and  in  doubtful  cases  one  should  use  a  dilu- 
tion of  1—40  or  1—60,  increase  the  time  to  one  or  two  hours,  and  re- 
quire a  distinct  result.     , 

Occurrence  of  the  Reaction. — Statistics  vary  considerably  regard- 
ing the  dates  of  occurrence  and  the  constancy  of  the  reaction  in  typhoid 
fever. 

Cabot  collected  over  3,000  cases  of  supposed  typhoid  fever,  of  which 
95  percent  gave  the  reaction  at  some  period  of  their  course,  while  in 
2,500  control  cases,  not  typhoid,  2  percent  gave  positive  reactions. 

Park  reports  positive  results  in  a  large  series. 

During  the  1st  week,  in  20  percent  of  the  cases. 
"        "    2d      "      "  60       "        "     " 
"        "    3d      "      "  80       "        "     "       " 
"        "    4th    "      "  90       "        "     "       " 
"    2d  month,"  75       "        "     "       " 

In  88  percent  of  hospital  cases  in  which  repeated  examinations  could 
be  made,  a  definite  reaction  was  obtained  at  some  period  of  the  disease. 

The  earliest  date  of  appearance  of  a  positive  reaction  has  not  been 
and  can  not  well  be  determined  in  the  human  subject,  but  in  animals 
inoculated  with  dead  typhoid  bacilli  the  reaction  appears  between  the 
third  and  eighth  days.  In  man  a  positive  reaction  has  been  found  by 
Johnston  and  Taggart,  and  by  Fraenkel,  on  the  second  day,  but  the  re- 
actions were  not  sharp.  Levy  found  the  first  distinct  reaction  on  the 
sixth  day  in  the  human  subject  inoculated  with  dead  typhoid  bacilli. 
It  may  be  found  before  the  appearance  of  rose  spots,  splenic  tumor,  or 
the  diazo  reaction  in  the  urine.  During  the  course  of  the  disease  the 
reaction  may  continue  without  interruption,  or  may  be  absent  one  day 
while  present  the  next.  It  may  be  absent  entirely  in  mild  cases,  may 
appear  only  in  a  relapse  (Lichtheim,  Breuer,  Thoinet),  may  disappear 
entirely  after  a  few  days  (Elsberg),  or  may  persist  for  months  or  even 
a  year.  Incomplete  reactions  have  been  reported  after  many  years. 
(Stewart.)  It  not  infrequently  appears  for  the  first  time  during  con- 
valescence or  may  exhibit  a  sudden  increase  at  this  time.  According 
to  Widal,  in  the  majority  of  cases  the  reaction  disappears  by  the  fif- 
teenth to  thirtieth  day  of  convalescence,  but  Stewart  believes  that  it 
persists  at  least  one  year  in  50  percent  of  the  cases,  for  two  years  in 
25  percent,  and  for  ten  years  in  5  percent.  His  conclusions  can  only 
apply  to  very  indistinct  reactions. 

Relation  of  the  Reaction  to  Other  Features  of  the  Disease. — In  some 
cases  the  reaction  is  most  intense  at  the  height  of  the  disease,  as  in  cases 
boserved  by  Jemma.     Widal  and  Sicard,  who  found  that  in  the  active 


276  WWALS  TEST. 

stage  a  dilution  of  1-60  or  1-80  does  not  usually  prevent  the  reaction, 
noted  a  marked  weakening  as  convalescence  proceeded,  some  cases  fail- 
iuo-  to  react  with  dilution  of  1—10.  They  noted  a  reaction  in  one  case 
with  a  dilution  of  1,000,  or  12,000.  Foerster,  who  found  a  reaction 
in  dilutions  varying  from  1-60  to  1,000,  or  5,000  could  not  detect  any 
relation  between  the  intensity  of  the  reaction  and  the  severity  of  the 
disease.  Pfeiffer  and  Kolle,  and  Foerster  have  shown  that  the  agglu- 
tinating power  has  no  relation  to  the  bactericidal  activity  of  the  serum. 

Effect  of  the  Typhoid  Serum  Upon  the  Colon  Bacillus. — Although 
Fraenkel  in  a  large  series  of  eases  reported  that  typhoid  serum  has  no 
marked  power  to  agglutinate  the  colon  bacillus,  and  recommended  the 
use  of  this  serum  in  the  separation  of  colon  from  typhoid  bacilli,  this 
claim  has  not  been  verified.  Stern  and  Biberstein  found,  very  shortly, 
five  cases  of  typhoid  fever  of  which  the  blood  serum  agglutinated  the 
colon  bacillus  even  more  powerfully  than  the  typhoid,  and  many  other 
observers,  including  Park,  Rodet,  Courmont,  Ustvedt,  Beusaude,  and 
Kuhnau,  have  had  similar  experiences  in  many  cases.  Baumgarten, 
therefore,  concludes  that  this  method  can  no  longer  be  accepted  as 
positive  proof  of  the  identity  of  Bacillus  coli  communis.  It  neverthe- 
less remains  true  that  a  germ  which  on  cultural  characters  falls  be- 
tween the  tvphoid  and  colon  groups,  is  almost  certainly  coli  communij<, 
if  it  is  not  agglutinated  by  a  well-tested  and  active  typhoid  serum. 
The  possibility  that  infection  by  the  colon  bacillus  is  intermingled 
with  that  of  Bacillus  tj/phosiis  in  enteric  fever  has  been  abundantly  con- 
sidered by  several  writers.  The  safest  method  of  identifying  the  colon 
bacillus  is  not  by  the  serum  of  a  case  of  typhoid  fever  but  by  the  serum 
of  an  animal  which  has  been  moculated  with  a  pure  culture  of  BojciUus 
typhoms. 

Reactions  in  Conditions  Other  than  Typhoid  Fever. — In  view  of  the 
fact  that  positive  reactions  have  been  obtiiined  both  with  healthy  serum 
and  in  diseases  other  than  typhoid  fever,  when  a  dilution  of  1-10  was 
used,  many  observers  have  recommended  that  higher  dilutions  only  be 
employed.  Thus  Schultz  obtained  complete  reactions  in  11  of  100 
cases  of  various  febrile  diseases  with  a  dilution  of  1—10  ;  in  7  cases, 
with  a  dilution  of  1—15  ;  and  in  3,  with  1—20  ;  while  a  faint  response 
followed  a  dilution  of  1—25  in  a  single  instance.  The  time  limit, 
howev'er,  was  1—2  hours.  In  single  cases  complete  reactions  with  di- 
lutions of  1-10  or  more  have  now  been  reported  in  so  many  cases  that 
it  is  no  longer  possible  to  refer  the  results  to  faulty  technique. 

Some  of  these  conditions  are  as  follows :  Septicemia  (Ferrand),  malaria 
(Bloch,  Villier,  Catrin,  and  the  writer),  pneumonia  (Kasel  and  Mann), 
tuberculosis  (Wesbrook,  Jez,  d'Espine),  otitis  (Stern),  influenza  (Wes- 
brook),  typhus  (Park),  meningitis  (v.  Oordt),  normal  serum  (Kuhnau). 

In  many  of  these  cases  the  dilutions  were  from  1—10  to  1—30,  or 
more,  and  the  clumping  was  prompt  and  complete. 

Negative  results  in  undoubted  cases  of  typhoid  fever  are  reported  by 
many  observers. 

Stewart,  using  dry  blood  in  538  cases,  found  typhoid  lesions  at  au- 


topsy  in  five  which  failed  at  three  periods  during  the  disease  to  give  a 
positive  reaction.  Thompson  also  reports  6  negative  results  in  163 
cases,  while  a  slight  reaction  was  obtained  in  12  percent  of  various 
conditions  other  than  typhoid  fever.  Ustvedt  encountered  a  peculiar 
epidemic  of  typhoid  fever  among  soldiers  in  which  4  of  15  cases 
failed  to  yield  a  reaction.  Total  failure  of  reaction,  under  full  pre- 
cautions, is  also  reported  in  single  cases  by  Artaud,  Haushalter,  Schu- 
macher, Fisher,  and  others. 

Value  in  Diagnosis. — The  difficulty  in  determining  the  value  of 
Widal's  test  in  diagnosis  arises  principally  from  the  divergent  opinions 
regarding  the  essential  features  of  a  complete  reaction.  Although  the 
belief  in  the  specific  quality  of  AVidal's  reaction  has  been  abandoned, 
the  test  remains  an  extremely  valuable  diagnostic  procedure  under 
several  conditions. 

It  must  be  granted  at  once  that  absolute  certainty  cannot  be  ascribed 
to  any  test  unless  the  dilution  has  been  very  high,  certainly  not  less 
than  1  to  60,  with  a  time  limit  of  not  more  than  15—30  minutes. 

A  positive  result  with  much  less  dilution  (1—30)  must  stand  as  al- 
most certain  evidence  that  the  disease  is  typhoid  fever.  Such  results 
are  usually  obtainable,  however,  only  after  the  disease  is  well  estab- 
lished and  its  clinical  symptoms  distinct.  Accordingly,  the  chief  value 
of  the  test  lies  in  its  capacity  to  distinguish,  during  the  height  of  the 
illness,  certain  conditions  such  as  acute  gastritis,  tuberculosis,  menin- 
gitis, and  pneumonia,  which  may  simulate  typhoid  fever. 

The  application  of  the  test  in  the  ear/y  diagno-ns  of  typhoid  fever 
has,  in  the  experience  of  most  observers,  proved  disajipointing.  It  is 
rarely  to  be  found  until  other  signs  render  the  diagnosis  very  probable, 
when  the  blood  test  may  often  be  added,  as  any  other  isolated  clinical 
symptom,  to  the  evidence  for  or  against  typhoid  fever. 

The  writer  believes,  however,  that  the  combination  of  an  indistinct 
serum  reaction,  diminution  of  fibrin,  absence  of  leucocytosis,  and 
presence  of  relative  or  absolute  lymphocytosis,  can  almost  never  be 
demonstrated  in  the  early  stages  of  any  obscure  febrile  disease  except 
typhoid  fever.  The  morphological  examination  of  the  blood  is,  therefore, 
a  valuable  adjimct  and  control  in  the  application  of  Widal's  test,  and 
the  writer  believes  that  in  doubtful  cases  it  should  never  be  omitted. 

Negative  results  are  of  very  moderate  import  until  the  third  or 
fourth  week,  and  unless  often  repeated,  while  some  reported  cases, 
often  fatal,  have  failed  at  any  time  to  yield  the  reaction. 

Summary. — The  most  reliable  method  for  clinical  purposes  is  the 
use  of  fresh  blood  diluted  with  water  in  a  graduated  pipette,  and  in- 
oculated as  a  hanging  drop  preparation.  Blood  or  blister  serum  should 
be  employed  for  more  extended  study,  while  the  use  of  dried  blood, 
sometimes  necessary,  gives  very  slightly  less  reliable  results. 

The  culture  should  be  grown  in  broth  at  36°  C,  24  hours  old, 
actively  motile,  and  of  moderate  virulence.  A  recognized  brand 
should  be  obtained  if  possible,  and  the  behavior  of  all  newly  isolated 
cultures  should  be  tested  before  use. 


278  WIDAL'S  TEST. 

A  positive  reaotion  consists  iu  the  complete  immobilization  of  all 
bacilli  and  the  compact  clumping  of  the  great  majority. 

A  time-limit  of  five  minutes  is  all  that  is  necessary,  with  dilutions  of 
1  to  20,  in  the  great  majority  of  positive  reactions.  With  higher  dilu- 
tion (1  to  40)  the  time  may  be  extended  to  30  minutes,  and  with  dilu- 
tion of  1  to  60,  to  2  hours.     (Me wins.) 

A  dilution  of  at  least  1  to  20  is  required  in  all  positive  reactions, 
with  which,  however,  occasional  errors  will  occur.  Dilutions  of  1  to 
30,  or  1  to  60,  are  to  be  strongly  recommended,  for  the  higher  the  di- 
lution the  more  certain  are  all  positive  results. 

A  negative  result  is  of  little  import  unless  obtained  during  the 
height  of  the  disease  (third  to  fifth  weeks)  and  on  repeated  examina- 
tions. In  the  great  majority  of  cases  the  reaction  disappears  within  a 
few  weeks  after  convalescence,  and  sev^eral  authentic  cases,  usually  fatal, 
have  not  given  a  positive  reaction  at  any  time. 

The  agglutinative  power  of  typhoid  serum  is  usually  slight  and 
transient  in  mild  cases  and  marked  and  persistent  in  severe  ones,  but 
bears  no  constant  relation  to  the  gravity  of  the  disease,  and  gives  no 
certain  prognostic  indications. 

Bibliography. 

Widal's  Test. 

Aehard,  Bensaude.     Compt.  Rend.  Soc.  Biol.,  1896, 5p.  940. 
Artaud.     Presse  Med.,  1898,  No.  18,  p.  106. 
Bensaiide.     L' Agglutination  des  Microbes,  Paris,  1897. 
Biberstein.     Zeit.  f.  Hygiene,  Bd.  27,  p.  847. 
Biggs,  Park.     Amer.  .Jour.  Med.  Sci.,  Vol.  113,  p.  274. 
Block.     Jour.  Amer.  .ALed.  Aasoc,  1897,  Vol.  29,  p.  7. 
Breuer.     Berl.  klin.  Woch.,  1896,  p.  1037. 
Catrin.     Soc.  des  Hop.,  1896,  p.  ()98. 

Courmont.  Compt.  Rend.  Soc.  Biol.,  1898,  p.  756.  Also,  Sero-prognostic  d.  1. 
fiev.  tvph.,  Paris,  1897. 

JDdepine.     Brit.  Med.  Jour.,  1897,  I.,  p.  1894. 

Durham.     Lancet,  1896,  II.,  p.  1746. 

Elsberg.     N.  Y.  Med.  Record,  Vol.  51,  p.  510. 

d.  Espine.     Rev.  med.  de  la  Suisse  Roinunde,  1898,  p.  113. 

Fei-rand.     Bull.  Soc.  d.  Hop.,  1897,  p.  104. 

Fischer.     Zeit.  f.  Hygiene,  Bd.  32,  p.  407. 

Foerster.     Zeit.  f.  Hvgiene,  Bd.  24,  p.  500. 

Fraenkd.     Munch.  liied.  Woch.,  1897,  p.  107. 

Gruber,  Durham.     Munch,  med.  Woch.,  1896,  pp.  206,  285. 

Orunbaum.     Brit.  Med.  Jour.,  1897,  II.,  p.  1852. 

Haushalter.     Presse  Med.,  1896,  p.  505. 

Jemma.     Cent.  f.  inn.  Med.,  1897,  p.  65. 

Jez.     Wien.  med.  Woch.,  1897,  p.  98  ;  1898,  p.  890. 

Johnston.     N.  Y.  Med.  Jour.,  1896,  Vol.  64,  p.  573. 

Johnston,  Tagqarl.     Brit.  Med.  Jour.,  1896,  II.,  p.  1629. 

Kolle.     Deut.  med.  Woch.,  1897,  p.  132. 

Kosel,  Mann.     Munch,  med.  Woch.,  1899,  p.  581. 

Kuhnau.     Berl.  klin.  Woch.,  1897,  p.  397. 

Levy.     Miinch.  med.  Woch.,  1897,  p.  1435. 

Lichtheim.     Cited  by  Foerster. 

Mewius.     Zeit.  f.  Hygiene,  Bd.  32,  p.  422. 

V.  Oordt.     Miinch.  med.  Woch.,  1897,  p.  327. 

Pfei^fer.     Zeit.  f.  Hygiene,  Bd.  18,  p.  1. 

Pfeiffer,  Kolle.     Deut.  med.  Woch.,  1896,  p.  185. 


BIBLIOGRAPHY.  279 

Bodet.     Compt.  Rend.  Soc.  Biol.,  1898,  p.  756. 

Scholtz.     Hvg.  Rundschau,  Bd.  8,  p.  417. 

Schumacher '    Zeit.  f.  Hygiene,  1899,  Bd.  30,  p.  364. 
t  Simon.     Cited,  Baumgarten's  Jahresber.,  1898,  p.  336. 

Stern.     Cent.  f.  Bact.,  1898,  p.  673. 

Stewart.     Amer.  Public  Health  Assoc,  Vol.  23,  p.  151. 

Thoinot.     Seinaine  Med.,  1896,  p.  504. 

Thompson.     Brit.  Med.  Jour.,  1897,  II.,  p.  1775. 

Ustvedt.     Cited,  Baumgarten's  Jahresber.,  1898,  p.  342. 

V.  d.  Veldes.     Acad.  med.  de  Belgique,  1897,  Mar.  27. 

Villiers.     Presse  Med.,  1896,  p.  54. 

Wesbrook.     Ref.  Cent.  f.  Bact.,  1898,  p.  713. 

Widal.     iSoc.  med.  des  Hop.,  1896,  p.  561.     ^Presse  Med.,  1897,  I.,  p.  c. 

Ziemke.     Deut.  med.  Woeh.,  1897,  p.  234. 
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3 


CHAPTER    XV. 
MISCELLANEOUS  INFECTIOUS  DISEASES. 

SEPTICEMIA,  PYEMIA,  OSTEOMYELITIS. 

Red  Cells. — In  no  other  diseases  do  the  red  cells  suffer  destruction  so 
constantly  and  to  such  an  extent  as  in  the  toxemia  of  diffuse  inflam- 
mation caused  by  the  common  pyogenic  bacteria.  This  fact  was  very 
early  noted,  Braidwood  finding  shrinkage  of  the  red  cells  and  absence 
of  rouleaux,  Mannassein  remarking  on  their  reduced  diameter,  and 
Quincke  and  Patrigeon  observing  extreme  loss  of  Hb  in  cases  of  py- 
emia. 

Hayera  and  Toenissen  placed  the  average  loss  of  red  cells  in  ordinary 
septic  fever  at  200,000  to  1,000,000  per  week,  while  a  continuous  dimi- 
nution was  found  to  persist  as  long  as  suppuration  continued.  That 
the  loss  of  red  cells  is  often  very  much  more  ra})id  than  Hayem  sup- 
posed is  shown  by  Grawitz's  remarkable  case,  in  which  fatal  puerperal 
sepsis  combined  with  considerable  hemorrhage  reduced  the  red  cells  in 
about  twenty-four  hours  to  300,000. 

Various  forms  of  acute  septicemia  not  infrequently  reduce  the  red 
cells  below  two  millions,  but  none  appear  to  act  more  violently  than  does 
puerperal  or  uterine  sepsis.  Hayem  ^  found  only  1.45  million  cells, 
20  percent  Hb,  in  a  recent  case  of  puerperal  sepsis.  Cabot  reports  1,8 
million  cells  from  a  "suppurating  fibroid."  The  writer  found  L6 
million  cells,  and  20  percent  Hb,  in  a  septic  form  of  endometritis,  not 
puerperal. 

When  the  suppurative  process  is  localized,  the  red  cells  are  usually 
found  to  be  only  slightly  affected,  but  with  the  first  appearance  of  the 
"  septic  "  condition  the  reduction  of  red  cells  promptly  begins,  Roscher 
finding  evidences  of  diminished  concentration  of  the  blood  within  the 
first  few  hours.  In  empyema,  suppuration  in  wounds,  pelvic  ab- 
scesses, appendicitis,  peritonitis,  etc.,  the  red  cells  are  seldom  markedly 
reduced,  while  the  usual  effects  of  fever  are  present  and  polycythemia 
is  often  found.  The  Hb  is,  as  usual,  more  susceptible  than  the  red 
cells,  and  its  loss  is  usually  out  of  proportion  to  that  of  the  red  cells, 
the  Hb-index  being  invariably  low. 

Timotjewsky  found  that  nucleated  red  cells  appear  promptly  in  the 
blood  of  dogs  after  moderate  injections  of  pyogenic  bacteria,  in  one  in- 
stance reaching  the  enormous  proportion  of  25,698  per  cmm.  Turk 
found  considerable  numbers  of  nucleated  red  cells  in  two  cases  of  sep- 
ticemia from  cystitis.     In  cases  of  intense  puerperal  sepsis  the  writer 


CHEMISTRY.  281 

has  usually  been  able  to  find  a  few  nucleated  red  cells,  but  they  have 
never  been  very  numerous. 

In  chronic  suppuration  the  red  cells  tend  to  diminish  as  long  as  the 
discharge  continues.  In  a  case  of  chronic  empyema  of  one  year's 
duration  the  writer  found  1.8  million  cells  and  25  percent  of  Hb,  but 
an  old  pelvic  abscess  discharging  a  small  quantity  of  pus  for  two  years 
had  induced  very  slight  anemia. 

Morphological  changes  in  the  red  cells  in  septicemia  are  usually 
present  in  moderate  degree.  Most  cases  show  a  pure  type  of  secondary 
chlorotic  anemia  with  marked  loss  of  Hb.  The  reduced  diameter  of 
the  anemic  cells,  previously  noted,  was  distinct  in  the  writer's  case  of 
septic  endometritis,  but  did  not  approach  the  grade  seen  in  some  forms 
of  primary  disease  of  the  blood.  In  severe  cases  many  cells  show 
granular  degeneration,  but  polychromasia  has,  in  the  writer's  experi- 
ence, not  been  prominent.  Marked  differences  in  the  size  and  shape 
of  the  cells  do  not  appear,  as  a  rule,  till  after  the  second  or  third  week 
of  a  severe  septic  process. 

Leucocytes. — A  considerable  number  of  cases  of  asthenic  septicemia 
run  their  course  without  leucocytosis,  or  with  distinct  reduction  of 
white  cells.  Such  cases  have  been  reported  by  Limbeck,  Krebs, 
Cabot,  and  Turk,  and  proving  invariably  fatal,  their  significance  is 
similar  to  cases  of  pneumonia,  diphtheria,  etc.,  with  hypoleucocytosis. 
In  Turk's  case,  and  in  one  observed  by  the  writer,  while  the  leucocytes 
were  sub-normal,  the  proportion  of  polynuclear  cells  was  very  high. 

The  great  majority  of  cases,  however,  show  pronounced  leucocytosis, 
which  is  usually  in  proportion  to  the  severity  of  the  disease.  Yet 
among  the  reported  cases  showing  leucocytosis  are  some,  like  Rieder's, 
in  which  very  severe  processes  either  failed  at  any  time  to  cause 
marked  increase  of  white  cells  or  else  the  examination  of  the  blood 
was  made  during  the  ante-mortem  decline  in  their  numbers.  Leuco- 
cytosis in  septic  processes  has,  therefore,  the  same  significance  as  in 
pneumonia  and  diphtheria. 

Regarding  the  more  minute  factors  determining  the  grade  of  leuco- 
cytosis little  is  definitely  known,  and  the  examination  of  the  blood 
must  be  interpreted  according  to  the  circumstances  in  each  case. 

While  the  rule  that  suppuration  induces  leucocytosis  is  almost  invaria- 
ble, it  must  be  remembered  that  leucocytosis  may  promptly  disappear  when 
the  exudation  ceases,  and  that  suppurations  involving  mucous  surfaces  may 
induce  ve7'y  slight  leucocytosis. 

The  polynuclear  leucocytes  are  almost  always  in  high  proportion  in 
cases  of  sepsis,  but  Klein  has  recently  described  a  case  of  hemorrhagic 
septicemia^  with  76  percent  of  eosins  in  the  pleural  exudate  and  40 
percent  in  the  blood. 

Chemistry. — The  loss  of  Hb  has  already  been  mentioned  as  one  of 
the  chief  alterations  in  the  blood  of  septicemia.  Its  solution  in  the 
plasma  and  the  occurrence  of  hemoglobinemia  is  observed  in  severe 
cases  with  rapid  destruction  of  blood.  In  cases  of  puerperal  sepsis,  or 
pyemia  in  infants,  the  solution  of  Hb  may  reach  a  very  extreme  grade. 


282  MISCELLANEOUS  INFECTIOUS  DISEASES. 

In  a  puerperal  case  the  writer  found  the  viscera  discolored,  and  so 
great  was  the  deposit  of  pigment  that  the  liver  and  spleen  closely  re- 
sembled, m  gross  and  microscopical  appearance,  the  organs  of  pernicious 
malaria.  The  increased  globulicidal  action  of  the  serum  in  these  cases, 
to  which  the  solution  of  red  cells  must  be  referred,  has  been  described 
by  Maragliano  and  others. 

An  increased  tendency  toward  crystallization  of  the  Hb  has  been 
noted  by  Bond  who,  in  examining  fresh  specimens,  found  a  rich  de- 
posit of  such  crystals  about  the  edge  of  the  cover-glass. 

Roscher  noted  in  severe  cases  a  very  rapid  lowering  of  the  specific 
gravity  of  the  blood,  beginning  a  few  hours  after  the  initial  symptoms. 
In  fatal  cases  the  dry  residue  of  the  whole  blood  fell  to  15  percent, 
while  in  favorable  cases  the  loss  of  solids  was  usually  much  less.  This 
rapid  and  extreme  loss  of  albumens  Roscher  and  Grawitz  regard  as 
a  valuable  prognostic  sign.  The  serum  also  usually  showed  a  pro- 
nounced loss  of  albumen,  proportionate  to  the  severity  of  the  septic 
process,  its  dry  residue  falling  from  10.5  percent  to  a  minimum  of 
6.25  percent.  Yet  in  a  very  severe  case  the  dry  residue  of  the  serum 
was  13.1  percent  of  its  weight,  which  Grawitz  explains  as  resulting 
from  the  solution  of  Hb, 

In  various  forms  of  pyogenic  infection  Livierato  found  an  excess  of 
glycogen  in  the  blood,  even  when  the  temperature  was  normal.  Gold- 
berger  and  Weiss  also  describe  in  the  leucocytes  during  abscess- for- 
mation a  reaction  to  iodine  either  in  the  form  of  a  diffuse  stain,  or  a 
granular  deposit.  They  also  find  many  brownish  staining  extra-cellu- 
lar granules  after  fractures,  and  believe  that  the  somewhat  obscure 
"  iodine  reaction  "  of  the  blood  may  be  made  of  value  in  the  diagnosis 
of  abscess,  fractures,  etc. 

Bacteriology. — The  frequency  with  which  specific  bacteria  can  be 
isolated  from  the  circulating  blood  in  cases  of  septic  infection,  in  spite 
of  the  vast  amount  of  study  devoted  to  the  subject,  still  remains  a 
matter  of  doubt. 

There  are,  on  the  one  hand,  a  large  number  of  studies  of  the  blood 
in  pyemia,  septicemia,  puerperal  fever,  osteomyelitis,  etc.,  reporting 
the  discovery  of  bacteria  in  a  large  proportion  of  cases,  while  in  many 
others,  reported  by  competent  observers,  very  uniformly  negative  re- 
sults were  obtained. 

On  reviewing  many  of  these  reports,  it  appears  that  the  majority  of 
them  must  be  set  aside  as  unreliable. 

Rosenbach,  Garrod,  Raskin,  Brunner,  Blum,  Czerniewski,  Eisel- 
berg,  Cautu,  Roux  and  Lannois,  Bommers,  Stern  and  Hirschler,  and 
others,  all  used  blood  squeezed  from  the  finger,  and  when  they  at- 
tempted to  demonstrate  the  same  germ  in  the  viscera  after  death,  were 
not  always  successful.  Many  of  their  successful  cultures  were  made 
only  a  few  hours  before  death.  AVhen  accurate  details  are  given,  as 
by  Czerniewsky,  it  appears  that  contaminations  by  clearly  non-patho- 
genic germs  frequently  occurred. 

On  the  other  hand,  Brieger,  drawing  blood  from  a  vein  by  a  steri- 


APPENDICITIS.  283 

lized  syringe,  obtained  negative  results  in  five  cases  of  puerperal  sepsis. 
Sanger,  by  the  same  method,  in  three  cases  of  osteomyelitis  found 
Staph  ijlocoGciis  aureus  or  albus  in  the  blood,  but  cultures  from  an  in- 
flamed joint  gave  only  Streptococcus  pyogenes.  Likewise  Kraus  re- 
ports six  positive  results  in  ten  cases  of  puerperal  sepsis,  but  one  was 
examined  post-mortem,  and  two  showed  only  Staphylococcus  albus. 
Cannon,  who  secured  a  number  of  successful  cultures  from  the  blood  in 
puerperal  sepsis,  osteomyelitis,  wound  infection,  etc.,  took  some  of  his 
specimens  from  a  puncture  of  the  skin,  and  Petruschky,  who  usually 
obtained  some  bacteria,  drew  the  blood  through  the  "disinfected" 
skin  by  means  of  a  wet  cup.  Sittmann,  accepting  as  genuine  the 
results  of  previous  investigators,  and  adding  nine  positive  cases  of  his 
own,  concludes  that  in  septico-pyemia  the  bacterial  agent  is  always  to 
be  found  in  the  blood,  and  that  its  presence  does  not  insure  a  fatal 
issue. 

Yet  later  observers,  as  Kuhnau,  would  not  accept  the  conclusions  of 
Sittmann  and  do  not  admit  much  significance  in  the  isolation  from  the 
blood  of  Staphylococcus  albus  or  the  colon  bacillus.  Kuhnau  examined 
the  blood  repeatedly  in  23  cases  of  septico-pyemia,  19  of  which  were 
fatal.  In  2,  Streptococcus  pyogenes  was  obtained,  in  one  Staphylococcus 
aureus.  Several  cultures  gave  non-pathogenic  germs,  among  them 
Staphylococcus  albus,  which  was  obtained  from  the  blood  but  not  from 
the  abscesses  after  death.  The  only  successful  cultures  were  made 
shortly  before  death,  or  in  one  case  during  a  chill. 

The  results  of  Kuhuau's  study  cannot  fail  to  raise  the  suspicion  that 
previous  investigators  have  been  too  lax  in  technique,  or  have  not 
fully  identified  their  species. 

From  the  review  of  the  above  studies  the  writer  draws  the  following 
conclusions  : 

1.  The  only  reliable  method  of  obtaining  blood  for  bacteriological 
examination  during  life,  is  to  draw  it  from  a  vein,  in  quantity  not  less 
than  5  cc,  through  the  thoroughly  sterilized  or,  better,  the  incised  skin, 
by  means  of  a  sterile  syringe  or  aspirator. 

2.  In  the  great  majority  of  cases  of  local  or  general  septic  infection, 
septico-pyemia,  septicemia,  pyemia,  diffuse  suppuration,  osteomyelitis, 
etc.,  bacteria  are  present  in  the  circulating  blood  only  for  short  periods 
and  at  infrequent  intervals,  most  frequently  during  chills. 

3.  A  few  hours  before  death  from  septic  infection,  various  bacteria, 
some  of  which  may  not  be  active  in  the  original  process,  make  their 
way  into  the  circulation. 

4.  In  a  very  moderate  number  of  cases  of  septic  infection,  especially 
those  which  are  not  attended  by  local  abscess  formation,  the  bacterial 
agent  may  be  isolated  from  the  blood  during  the  progress  of  the  dis- 
ease. 

APPENDICITIS. 

Special  interest  attaches  to  the  examination  of  the  blood  in  appendi- 
citis, and  Cabot,  in  a  study  of  72  cases,  has  pointed  out  conditions  in 


284  MISCELLANEOUS  INFECTIOUS  DISEASES. 

which  the  information  thus  gained  may  be  of  great  value  in  diagnosis. 
Quoting  largely  from  his  observations  it  appears  that : 

A  catarrhal  appendicitis  is  rarely  accompanied  by  leucocytosis,  one 
case  showing  14,000  cells.  The  majority  of  more  severe  cases,  on  the 
second  to  fourth  days  show  leucocytosis,  from  15,000  to  24,000.  More 
marked  leucocytosis  (maximum  52,000)  was  always  associated  witii 
large  abscesses  or  peritonitis.  Twelve  of  15  cases  with  less  than  15,- 
000  cells  recovered  without  operation  or  would  probably  have  done  S(» 
as  no  pus  was  found  by  the  surgeon.  Four  cases  with  general  purulent 
peritonitis  failed  to  show  leucocytosis,  and  other  cases  with  peritonitis 
gave  slight  leucocytosis  (14,800,  16,000).  Other  cases  illustrated  the 
fact  that  when  pus  ceases  to  be  exuded  the  leucocytosis  may  subside. 
After  successful  operations  the  leucocytosis  usually  declined,  but  was 
subject  to  considerable  oscillations,  not  always  referable  to  collections 
of  pus. 

It  therefore  appears  that  the  interpretation  to  be  placed  upon  the 
examination  of  the  blood  in  appendicitis  is  extremely  variable.  With 
leucocytosis  ranging  between  14,000  and  16,000  cells,  the  condition 
may  be :  (1)  Catarrhal  appendicitis,  (2)  perforative  inflammation  with 
abscess,  (3)  large  abscess,  (4)  general  peritonitis.  Moreover,  the 
character  of  the  leucocvtosis  in  those  dano^erous  forms  of  the  disease 
which  pursue  a  mild  course  for  a  time  but  suddenly  develop  peritonitis 
from  perforation  is  not  yet  clear.  It  appears  that  the  blood,  as  well  as 
most  other  symptoms,  equally  fails  to  give  warning  of  this  outcome. 
Nor  can  the  question  of  operation  in  frank  cases  be  decided  from  the 
blood  examination,  as  one  of  Cabot's  cases  with  33,000  leucocytes  re- 
covered without  interference. 

In  differential  diagnosis  a  positive  conclusion  seems  to  be  warranted 
only  in  those  cases  which  show  well-marked  leucocytosis,  from  the 
presence  of  which  it  is  possible  to  rule  out  nearly  all  forms  of  typhoid 
fever  and  most  but  not  all  cases  of  fecal  impaction.  Hubbard  has 
offered  some  very  practical  comments  on  the  limitations  of  blood  ex- 
aminations in  this  field. 

ABSCESS  FORMATION. 

Active  suppuration  in  a  confined  space  is  almost  invariably  accom- 
panied by  distinct  leucocytosis.  Cabot  has  remarked  on  the  high  leu- 
cocytosis usually  observed  with  very  limited  suppurative  foci  in  sub- 
cutaneous, submucous,  or  interstitial  connective  tissues,  and  reports 
very  considerable  increase  of  white  cells,  with  furuncle,  carbuncle,  and 
abscess  of  vulva,  vagina,  middle  ear,  uterus.  Fallopian  tube,  ovary,  lung, 
brain,  parotid  gland,  neck,  and  in  pectoral,  psoas,  and  perinephritic 
regions.  The  writer's  experience  in  a  considerable  variety  of  such 
conditions  fully  accords  with  these  reports,  leucocytosis  having  been 
present  in  the  active  stages  of  all  such  processes,  but  subsiding  slowly 
or  rapidly  after  operation  or  after  the  exudative  process  had  ceased. 
An  important  exception  to  the  rule  was  found  in  abscess  of  the  liver 
with  muco-purulent  exudate.     (See  Liver.) 


ACUTE  RHEUMATISM.  285 

ERYSIPELAS. 

A  slight  elimination  of  red  cells  and  Hb  was  observed  in  severe 
cases  by  Malassez,  Hayem,  and  Reinert.  In  mild  cases  the  fibrin  is 
not  affected,  but  in  severe  forms  of  the  infection  its  formation  is  much 
increased.      (Turk.) 

Leucocytosis  occurs  in  nearly  all  cases,  but  Rieder  reported  one  in- 
stance of  facial  erysipelas  with  a  temperature  of  39°  C.  and  6,800 
white  cells.  Turk  observed  one  case  of  considerable  extent  with  tem- 
perature 38.5-40.2°  and  leucocytes  between  7,000  and  8,900.  Later 
the  temperature  rose  to  40.5°  and  the  leucocytes  to  10,100.  Zappert, 
also,  observed  two  febrile  cases  with  subnormal  numbers  of  white  cells 
(5,500-6,500).  Hayem  found  between  7,000-8,000  leucocytes  in  very 
mild  cases,  but  12,000-20,000  when  the  rash  was  extensive. 

Most  of  the  cases  of  Pee,  Rieder,  Ehrlich,  Limbeck,  and  Cabot,  gave 
leucocytosis  of  moderate  grade  but  in  proportion  to  the  severity  of  the 
disease.  Higher  leucocytosis  was  observed  by  Halla  in  uncomplicated 
facial  erysipelas  and  in  a  case  complicated  by  pneumonia  (23,000). 
Suppuration  raised  the  count  to  39,600  in  a  case  of  Reinert's,  and  to 
59,400  in  one  of  Epstein's. 

When  the  total  increase  is  considerable  the  polynuclear  cells  are 
much  increased  in  proportion,  but  with  slight  increase  the  polynuclear 
cells  are  usually  unaffected.  Eosins  are  usually  diminished  or  absent. 
(Zappert,  Turk.) 

Negative  bacteriological  examinations  of  the  blood  in  erysipelas  are 
reported  by  Petruschky  in  three  cases  and  by  Kraus  in  one  case. 

ACUTE   RHEUMATISM. 

A  much  increased  formation  of  fibrin  has  been  noted  by  many  ob- 
servers, Halla,  Hayem,  Berggrun,  Turk. 

Red  Cells. — It  is  a  general  clinical  rule  that  patients  who  pass 
through  an  attack  of  acute  rheumatism  become  distinctly  anemic.  In 
many  cases  of  ordinary  severity  the  loss  of  red  cells  is  slight,  while  the 
Hb  falls  to  65-80  percent. 

In  more  severe  cases  Hayem  seldom  found  more  than  4  million  cells. 
Sorensen  found  an  average  of  4.16  millions  in  8  cases.  \\\  prolonged 
and  relapsing  cases  the  red  cells  not  infrequently  fall  slightly  below  4 
millions.  Yet  in  few  of  the  reported  studies  are  the  examinations 
sufficiently  extensive  to  show  that  such  anemia  is  referable  to  the  acute 
disease.  Turk,  while  admitting  the  usual  presence  of  anemia  even 
during  the  febrile  period,  saw  a  distinct  increase  in  red  cells  beginning 
with  defervescence,  and  in  Cabot's  cases  it  does  not  appear  either  that 
there  was  any  uniform  loss  of  red  cells  or  that  the  cases  of  long  stand- 
ing were  invariably  the  more  anemic.  It  seems,  therefore,  that  the 
severity  of  post-rheumatic  anemia  has  been  overestimated. 

The  Hb  suffers  more  severely  and  much  more  constantly  than  the 
red  cells.     Cabot's  average  in  31  cases  was  67  percent,  and  a  few  cases 


286  MISCELLANEOUS  INFECTIOUS  DISEASES. 

fell  below  60  percent,  while  Turk  found  between  60  and  SO  percent. 
Prompt  use  of  salicylates  prevented  the  loss  of  Hb  in  a  case  of  Lichten- 
stern's,  and  apparently  also  in  one  of  Cabot's. 

In  convalescence  the  restoration  of  Hb  remains  considerably  behind 
that  of  the  red  cells. 

Leucocytes. — In  mild  cases  without  exudation  there  is  usually  no 
distinct  leucocytosis.  (Pee,  Rieder.)  When  fever  and  swelling  of  joints 
exist  there  is  almost  always  an  increase  to  10,000  or  15,000  cells. 
Turk  insists  that  when  the  leucocytes  reach  20,000  or  more  there  are 
nearly  always  complications,  such  as  pleurisy,  pericarditis,  or  pneu- 
monia. Hayem  also  found  17,000-18,000  cells  in  moderately  severe 
attacks,  and  as  high  as  25,000,  only  in  extremely  severe  and  cerebral 
types  of  the  disease.  Cabot  reports  21,000-31,000  cells  in  6  cases, 
one  complicated  by  acute  endocarditis,  while  in  the  others  no  complica- 
tion was  mentioned.  The  writer,  from  the  examination  of  40  cases,  in 
1893,  can  support  Turk's  statement,  having  found  signs  of  pneumonia, 
or  pericarditis,  or  hyperpyrexia,  whenever  the  leucocytes  rose  above 
20,000.  The  pneumonic  signs  however  were  not  always  those  of  com- 
plete consolidation. 

With  defervescence  the  leucocytes  promptly  fall  to  normal,  and  in 
relapses  are  much  less  affected  than  by  initial  attacks.      (Turk.) 

Types  of  Leucocytes. — When  the  white  cells  do  not  greatly  exceed 
10,000,  the  proportions  of  the  various  forms  are  not  much  disturbed. 
With  distinct  leucocytosis  the  proportion  of  polynuclear  cells  rises  to 
a  considerable  height.  Eosins  are  absent  only  in  the  early  stages  ; 
later,  in  spite  of  fever  and  exudation  they  are  always  present  in  mod- 
erate numbers,  while  after  defervescence  most  cases  show  a  distinct 
tendency  toward  eosinophilia.  (Turk.)  In  one  of  Turk's  cases  there 
were  13.8  percent  of  eosins,  and  in  another  8.33  percent,  shortly  after 
defervescence.  This  observer  believes  that  a  high  proportion  of  eosino- 
phile  cells  during  the  febrile  period  is  a  good  prognostic  sign,  and  oc- 
curs principally  in  self-limiting  cases. 

Bacteriology. — In  several  studies,  reviewed  by  Sittmann,  various 
pathogenic  bacteria  were  obtained  from  the  circulating  blood,  but  these 
cases  have  later  been  classed  as  examples  of  septicemia  and  not  of 
articular  rheumatism.  The  principal  bacteriological  studies  of  the 
blood  of  acute  rheumatism  are  those  of  Sittmann,  Singer,  Kraus,  and 
Kuhnau.  Sittmann  obtained  negative  results  from  repeated  cultures 
in  5  cases,  and  Kraus  in  12  cases.  Singer  conducted  an  elaborate  study 
of  the  blood  and  urine  in  60  cases,  but  while  he  found  Staphylococcus 
a/6M.s  in  several  instances,  this  germ  was  probably  a  contamination  from 
the  skin.  In  one  case  Streptococcus  pyogenes  was  isolated,  but  the  history 
shows  the  patient  to  have  been  suffering  from  hemorrhagic  septicemia 
and  endocarditis. 

Even  more  conclusive  were  the  totally  negative  results  obtained  by 
Kuhnau  in  67  cases  representing  all  types  of  the  disease  and  many 
complications. 

There  seems  therefore  to  be  no  longer  any  room  to  doubt  that  the 
blood  in  acute  articular  rheumatism  is  sterile. 


INFLAMMATIONS  OF  SEROUS  MEMBRANES.  287 

TONSILLITIS. 

Follicular  tonsillitis  usually  causes  moderate  leucocytosis,  seldom 
rising  above  15,000  (Halla,  Pick,  Pee),  yet  in  mild  cases  it  may  be 
absent  (Cabot).  In  phlegmonous  tonsillitis  more  marked  leucocytosis, 
reacliing  20,000  cells  or  more,  usually  occurs.     (Pee,  Eieder.) 

The  leucocytosis  is  generally  more  marked  than  in  diphtheria  with 
equal  constitutional  disturbances.      (Pee.) 

WHOOPING-COUGH. 

Meunier  has  observed,  in  30  cases  of  pertussis  in  children  of  various 
ages,  a  pronounced  or  extreme  leucocytosis  which  "/«/•  exceeds  the  in- 
crease found  in  any  other  afebrile  disease  of  the  resjyiratory  passages J^ 

The  grade  of  leucocytosis  varies  with  the  age  of  the  patient,  being 
most  marked  in  children  under  four  years,  and  usually  reaching  a 
slightly  lower  figure  in  children  from  four  to  seven  years.  It  appears 
in  the  catarrhal  stage  before  the  characteristic  cough,  when  its  demon- 
stration may  be  made  of  diagnostic  value,  and  disappears  slowly  with 
the  improvement  of  the  disease.  It  is  little  influenced  by  complica- 
tions. The  average  leucocytosis  was  27,800,  but  in  several  cases  40,- 
000  cells  were  found,  and  in  one  51,150.  The  lowest  figure  obtained 
during  an  active  period  was  15,500.  The  proportion  of  lymphocytes 
was  always  high,  averaging  53.8  in  a  portion  of  the  cases,  while  the 
polynuclear  cells  maintained  a  low  average  (39  percent),  and  the  eosins 
were  scarce  or  normal  in  number.  Meunier  refers  the  lymphocytosis 
to  hyperplasia  of  bronchial  lymph  nodes. 

De  Amicis  and  Pacchioni  also  report  marked  leucocytosis  in  whoop- 
ing-cough, beginning  in  the  first  days  of  the  disease,  reaching  its  height 
in  the  spasmodic  stage,  and  being  sometimes  prolonged  after  the  cessa- 
tion of  the  typical  cough.  Cabot  found  12,600  white  cells,  and  78  per- 
cent Hb  in  a  girl  of  6  years. 

INFLAMMATIONS    OF    SEROUS    MEMBRANES. 

PLEURISY,  PERICARDITIS,   PERITONITIS. 

Serous  inflammations  of  the  large  serous  membranes  usually  cause  a 
slight  increase  of  leucocytes  in  the  blood  during  the  acute  febrile  stages. 
Thus,  Hayem  found  between  7,500  and  12,000  leucocytes  in  acute 
pleurisy,  liieder  11,000-13,000,  and  some  of  Cabot's  early  cases  regis- 
tered as  high  as  15,000.  Higher  leucocytosis  belongs  to  the  more 
severe  inflammations,  with  temperatures  reaching  101—104°  F.  In  two 
cases  of  sero-fibrinous  pleurisy  Limbeck  found,  with  a  temperature  of 
38-8°  C,  18,000-19,000  leucocytes,  and  with  a  temperature  of  41.5° 
C,  22,000  cells.  The  grade  of  leucocytosis  excited  by  fibrinous  pleu- 
risy, pericarditis,  etc.,  has  apparently  not  been  determined.  The  in- 
flammation stands  in  an  intermediate  position  in  point  of  intensity. 


288  MISCELLANEOUS  INFECTIOUS  DISEASES. 

With  purulent  processes  the  leucocytosis  is  usually  much  higher.  In 
1893  the  writer  found  no  diiference  in  the  leucocytosis  of  pneuraonia 
from  that  of  idiopathic  empyema  and  purulent  pericarditis.  All  the 
cases  of  pericarditis  were  complicated  by  pneumonia  or  rheumatism 
and  gave  very  high  counts  (maximum  60,000).  The  writer  has  seen 
one  case  of  very  rapidly  fatal  empyema,  yielding  Streptococcus  pyogenes 
in  cultures,  in  which  there  was  scanty  purulent  exudate  and  slight  and 
diminishing  leucocytosis. 

In  purulent  peritonitis,  also,  leucocytosis  is  not  infrequently  absent. 

After  the  exudative  process  has  ceased  the  leucocytosis  subsides, 
very  rapidly  in  the  case  of  serous  exudates  and  usually  more  slowly 
with  purulent  processes.  The  majority  of  serous  effusions  are  there- 
fore encountered,  as  in  Halla's  and  Cabot's  cases,  when  the  leucocytes 
are  normal  in  number,  nor  is  it  rare  to  find  extensive  empyema  with 
no  excess  of  white  cells  in  the  blood. 

Tuberculous  inflammations  of  serous  membranes,  when  pure  and  un- 
complicated, are  seldom  accompanied  by  leucocytosis.  Limbeck  reports 
4,600  cells  in  a  case  of  tuberculous  peritonitis. 

In  serous  pleurisy  it  is  seldom  possible  to  distinguish  the  quiescent 
stages  of  simple  serous  effusions  from  beginning  tuberculous  exudates, 
and  the  examination  of  the  blood  cannot  prove  of  much  value  in 
diagnosis. 

In  a  case  of  empyema  in  which  tubercle  bacilli  were  extremely 
numerous,  the  writer  found  moderate  intermittent  leucocytosis  (maxi- 
mum, 18,000). 

GONORRHEA. 

In  acute  gonorrheal  urethritis  the  red  cells  remain  unaffected.  A 
moderate  leucocytosis  is  usually  observed  in  severe  febrile  cases,  and  is 
markedly  increased  by  many  complications,  including  cystitis,  epididy- 
mitis, orchitis,  etc. 

The  poly  nuclear  cells  are  in  the  usual  excess,  while  eosins,  although 
sometimes  very  abundant  in  the  urethral  discharge  (Bettman),  usually 
remain  within  moderate  limits  (.5  to  11.5  percent)  in  the  blood  (Vor- 
bach).  Bettman,  however,  while  finding  that  there  is  no  relation 
between  the  eosins  of  the  discharge  and  those  in  the  blood,  believes 
eosinophilia  is  usually  present  in  gonorrhea,  especially  in  posterior 
urethritis.  He  found  25  percent  of  eosins  in  the  blood  in  a  case  of 
gonorrheal  epididymitis. 

In  gonorrheal  rheumatism  the  changes  in  the  blood  are  similar  to 
those  of  the  idiopathic  joint  affections. 

The  gonococcus  has  several  times  been  isolated  from  the  blood  in 
gonori'heal  endocarditis  (q.  v.). 

YELLOW   FEVER. 

From  Jones'  interesting  observations  about  yellow  fever,  it  would 
appear  that  anemia  is  infrequent,  that  fibrin  formation  is  deficient,  that 


EPIDEMIC  INFLUENZA.  289 

the  globulicidal  action  of  the  serum  is  very  greatly  increased,  and  that 
cholemia  is  responsible  for  some  of  the  changes  observed  in  the  red 
cells  before  and  after  shedding.  "  When  a  drop  of  blood  from  a 
yellow  fever  patient  falls  upon  blotting  paper,  a  dark  brownish  ring 
due  to  diffusion  of  bile-stained  plasma  spreads  about  the  central  mass 
of  blood  cells."     (Jones.) 

Pothier  examined  in  some  detail  the  blood  of  154  cases.  The  red 
cells  never  fell  below  4.28  millions  and  in  one  fatal  case  were  normal. 
The  Hb  suffered  a  considerable  loss  during  the  course  of  the  disease, 
registering  between  50  and  72  percent.  In  the  above  fatal  case  90 
percent  of  Hb  was  found.     The  restoration  of  the  Hb  was  slow. 

Morphological  changes  in  the  red  cells  were  usually  absent,  but  the 
presence  of  normoblasts  was  noted  in  a  few  specimens. 

The  leucocytes  fell  between  4,660  and  20,000.  The  polynuclear 
cells  were  found  in  high  proportions  in  some  of  the  slides  from  these 
cases,  examined  by  Cabot,  while  in  others  their  proportions  were 
normal.  Eosins  were  very  scarce  and  myelocytes  were  found  in  one 
case.  The  writer  examined  dry  specimens  of  the  blood  of  two  rapidly 
fatal  cases  of  yellow  fever  brought  from  Rio  Janeiro  by  Dr.  J.  M. 
Masury,  and  noted  slight  hemoglobinemia,  and  hypoleucocytosis. 

Pothier  tested  the  action,  of  the  serum  of  some  of  his  patients  on  cul- 
tures of  Sanarelli's  bacillus,  but  the  results  did  not  indicate  the  presence 
of  any  specific  power  in  the  blood. 

TYPHUS    FEVER. 

In  4  cases  the  writer  fouud  between  5,000  and  9,000  leucocytes. 
The  patients  were  adults,  the  examinations  were  made  during  the  high 
fever  of  the  early  period  of  the  disease,  and  at  least  two  of  the  patients 
died. 

Tumas  followed  one  fatal  case  during  a  three  weeks'  course,  observ- 
ing a  steady  reduction  of  red  cells  from  4.4  to  3.1  millions,  of  Hb  from 
80-50  percent,  and  hypoleucocytosis,  9,600-1,600. 

EPIDEMIC    INFLUENZA. 

The  scanty  reports  of  the  condition  of  the  blood  in  epidemic  influ- 
enza indicate  that  the  disease  in  uncomplicated  form  fails  to  cause  leu- 
cocytosis.  This  fact,  while  in  accordance  with  the  catarrhal  character 
of  the  essential  lesions,  is  somewhat  difficult  to  reconcile  with  acute  in- 
fectious nature  of  the  disease.  Grippe  appears  to  be  the  only  bacterial 
disease,  beginning  acutely  with  marked  chill,  which  fails  to  induce  leu- 
cocytosis. 

The  absence  of  leucocytosis  in  grippe  was  first  demonstrated  by 
Rieder"  who,  in  7  cases,  found  that  the  white  cells  at  the  acme  of  the 
disease  were  reduced  in  number  (7,000-2,800).  In  the  catarrhal  pneu- 
monia which  complicates  the  disease  and  which  is  distinguished  by 
signs  of  incomplete  consolidation,  he  found  little  or  no  leucocytosis, 
19 


290  MISCELLANEOUS  INFECTIOUS  DISEASES. 

maximum,  13,000.  In  lobar  pneumonia  following  grippe  the  usual 
leucocytosis  was  observed.  In  1893  the  writer  found  no  difference  in 
the  leucocytosis  of  lobar  pneumonia  following  grippe  from  that  of  pri- 
mary pneumonia.  Cabot  reports  the  examination  of  the  blood  in  67 
cases,  most  of  which  showed  normal  or  reduced  numbers  of  white  cells, 
and  when  there  was  slight  leucocytosis  (maximum  14,000)  complica- 
tions were  usually  present. 

Bacteriological  Examination. — In  a  considerable  proportion  of 
cases  Canon,  Klein,^  Hirschfeldt,  Bruschettini,  and  others,  have  ob- 
tained from  the  blood  cultures  of  what  they  believed  to  be  PfeiflPer's 
bacillus. 

Pfeiifer  and  Kruse,  and  others  were  unable  to  isolate  the  bacillus  of 
influenza  from  the  blood,  and  denied  the  identity  of  some  of  the  germs 
obtained  from  the  blood  by  others. 

Recently  Kuhnau  has  added  12  negative  results,  and  there  seems  little 
reason  to  doubt  that  the  bacillus  of  influenza  has  no  special  capacity  to 
invade  the  blood  stream. 

TETANUS. 

Cabot  reports  70  percent  of  Hb,  11,900  leucocytes,  and  persistence 
of  eosinophile  cells,  in  a  fatal  case  of  tetanus  treated  by  antitoxine. 

BUBONIC    PLAGUE. 

Aoyama  in  1895  examined  the  blood  of  many  cases,  reporting  four 
in  full.  The  red  cells  varied  from  4.4  to  8.1  million,  the  latter  in  a 
case  which  recovered,  and  in  the  report  of  which  no  cause  of  polycy- 
themia is  apparent.  The  Hb  was  normal.  The  leucocytosis  also  was 
reported  to  have  reached  a  very  high  grade,  110,000-200,000  in  three 
cases,  and  20,000  in  a  convalescent  case.  Polynuclear  cells  made  up 
the  bulk  of  the  increase,  but  large  and  small  lymphocytes  were  numer- 
ous, and  eosins  scarce. 

The  Austrian  Pest-Commission  reported  only  moderate  leucocytosis 
in  the  majority  of  cases.      (Wien.  klin.  Woch.,  1897,  p.  465.) 

Zabolotny  studied  the  reaction  of  the  blood  serum  on  cultures  of 
the  bacillus.  During  the  first  week  no  effect  was  observed  even  with 
a  dilution  of  1-6  ;  in  the  second  week  reactions  were  obtained  with 
dilutions  of  1-10;  in  the  third  week,  with  1-25  ;  in  the  fourth  week, 
with  1-50.  The  reaction  was  most  marked  in  the  severer  cases,  and 
the  blood  serum  of  the  cadaver  was  inert. 

MALTA   FEVER. 

The  hemorrhages  which  mark  the  severer  forms  of  this  malady  com- 
monly give  rise  to  severe  anemia.  Bruce  places  the  average  number 
of  red  cells  at  3.5  millions,  and  reports  the  absence  of  leucocytosis  and 
occasional  presence  of  free  pigment  in  the  blood.  In  a  prolonged  case 
without  hemorrhages,  Musser  and  Sailer  found  5.05  million  red  cells, 
60  percent  Hb,  11,564  leucocytes,  all  varieties  being  in  normal  pro- 
portions. 


BIBLIOGRAPHY.  291 

Wright  and  Smith  found  that  the  blood  serum  of  cases  of  Malta 
fever  agglutinates  cultures  of  Bacillus  melitensis,  and  diagnoses  of  the 
disease  have  been  made  by  this  method  by  Miisser  and  Sailer,  Cox, 
and  others.  A  dilution  of  serum  1—50  should  give  a  prompt  reaction, 
while  typhoid  serum  has  no  eifect. 

ACTINOMYCOSIS. 

The  writer  found  21,500  leucocytes  in  a  case  of  pulmonary  acti- 
nomycosis, clinically  resembling  acute  phthisis,  and  Cabot  reports  a 
case  of  actinomycosis  of  liver  with  3,700  white  cells. 

The  markedly  purulent  character  of  the  exudate  excited  by  the  ray 
fungus  explains  the  grade  and  character  of  the  leucocytosis.  Bier- 
freund  found  marked  chlorotic  anemia  in  actinomycosis,  the  Hb  regis- 
tering 30-50  percent. 

GLANDERS. 

Cabot  reports  11,600-13,600  leucocytes  in  a  fatal  case  of  very  acute 
glanders.  Duval  isolated  the  bacillus  of  glanders  from  the  blood  dur- 
ing life,  and  Noniewitch  reports  that  in  fatal  cases  in  horses,  the  bacilli 
can  be  found  in  the  circulating  blood,  usually  wdthin  the  leucocytes. 

ANTHRAX. 

Anthrax  in  some  lower  animals  frequently  develops  into  a  pro- 
nounced bacteriemia  early  in  the  disease.  Man,  however,  usually  ex- 
hibits only  a  moderate  grade  of  susceptibility  to  the  infection  and  the 
majority  of  cases  recover  after  excision  of  local  foci  of  infection.  Al- 
though it  is  probable  that  in  the  severe  septicemic  forms  of  the  disease 
anthrax  bacilli  may  multiply  in  the  general  blood  stream  early  in  the 
disease,  the  literature  appears  to  contain  very  few  reports  of  competent 
bacteriological  analyses  of  the  blood  in  such  conditions.  The  rather 
frequent  impression  that  the  diagnosis  of  anthrax  can  be  made  by 
morphological  examination  of  a  drop  of  blood  from  the  general  circu- 
lation is  almost  entirely  without  foundation,  as  the  great  majority  of 
cultures  of  the  blood,  even  in  severe  cases,  have  been  found  sterile. 
Only  in  the  late  stages  of  some  septicemic  cases  in  man  do  the  bacteria 
invade  the  circulation  and  yield  positive  cultures  of  the  blood.  Such 
a  case  is  that  of  Blumer  and  Young,  who  report  successful  cultures, 
and  claim  to  have  identified  the  germ  in  blood-smears  during  life,  but 
the  time  before  death  was  not  stated. 

Ante-mortem  invasion  of  the  blood  by  anthrax  in  man  is  apparently 
not  much  if  any  more  abundant  than  with  some  other  infections,  and 
even  post-mortem  cultures  are  frequently  negative. 

Detailed  clinical  examinations  of  the  red  cells  and  leucocytes  in  the 
blood  of  anthrax  are  still  wanting. 

Bibliography. 

Miscellaneous  Infectious  Diseases. 
Aoyama.     Mittheil.  a.  d.  kaiserl.  Japanisch.  Univers.,  1895,  Ed.  III.,  No.  2. 
Bein.     Zeit.  f.  klin.  Med.,  Bd.  17,  p.  545. 


292  MISCELLANEOUS  INFECTIOUS  DISEASES. 

Bettman.     Archiv  f.  Derm,  et  Syph.,  Bd.  49,  p.  227. 

Bierfreimd.     Arcliiv  f.  C'hirurg.,  Bd.  41. 

Blum.     Miinch.  med.  Woch.,  1893,  p.  297. 

Blumer,   Young.     Johns  Hopkins  Bulletin,  1885,  p.  127. 

Bommers.     Deut.  med.  Woch.,  1893,  p.  552. 

Bond.     Lancet,  1887,  II.,  pp!  509,  557. 

Braidwood.     On  Pyemia,  etc.,  London,  1868. 

Brieger.     Charite-Annalen,  1886,  p.  198. 

Bruce.     Lancet,  1892,  II.,  p.  1101.     Annal.  de  I'lnstitut  Easteur,  1893. 

Brunner.     Wien.  klin.  Woch.,  1891,  p.  391. 

Bruschettini.     Kit'.  Medica,  1893,  No.  186. 

Cannoa.     Deut.  Zeit.  f.  Chirurg.,  Bd.  33,  p.  571. 

Canrm.     Virchow's  Archiv,  Bd.  131,  p.  401. 

Ointu.     Kif.  Med.,  1892,  II.,  p.  243. 

Cox.     Philadelphia  Med.  Jour.,  Vol.  4,  p.  491. 

Czerniewsky.     Archiv  f.  Gynecol.,  1888,  p.  73. 

Be  Amicis,  Pacchioni.     Ref.  in  Amer.  Jour.  Med.  Sci.,  Vol.  119,  p.  599. 

Duval.     Archiv  de  Med.  exper.,  1896,  p.  361. 

Ehiiich.     Charite-Annalen,  Bd.  12,  p.  288. 

Eiselberg.     Wien.  klin.  Woch.,  1890,  p.  731. 

Epstein.     Allg.  Wien.  med.  Zeit.,  1889,  No.  43. 

Friedrich.     Arbeit,  a.  d.  kaiserl.  Gesundheitsampte,  1890,  p.  250. 

Garrod.     Fort.  d.  Med.,  1885,  p.  165. 

Ooldberger,  Weiss.     Wien.  klin.  Woch.,  1897,  p.  601. 

Halla.     Zeit.  f.  Heilk.,  Bd.  4. 

Hayem.     '  Du  Sang.     ^  Med.  Moderne,  1897. 

Hirschfeldt.     Baumgarten's  Jahresber.,  1893,  p.  206. 

Hubbard.     Boston  Med.  and  Surg.  Jour.,  Vol.  142,  p.  409. 

Jones.     Jour.  Amer.  Med.  Assoc,  Vol.  24,  p.  402. 

Klein.     iCent.  f.  inn.  Med.,  1899,  p.  97.     ^Baumgarten's  Jahresber.,  1893,  p.  206. 

Kraus.     Zeit.  f.  Heilk.,  Bd.  17,  p.  117. 

Krebs.     Diss.  Berlin,  1893. 

Kruse.     Cent.  f.  Bact.,  Bd.  7,  p.  657. 

Kuhnau.     Zeit.  f.  Hygiene,  Bd.  25,  p.  492. 

Livierato.     Deut.  Archiv  f.  inn.  Med.,  Bd.  53,  p.  303. 

MalasAcz.     Archiv  de  Physiol.,  1874,  p.  32. 

Manassein.     U.  d.  Verand.  in  d.  Dimens.  d.  rot.  Blutkorp.,  Tubingen,  1872. 

Maragliano.     Cong.  f.  inn.  Med.,  1892. 

Meunier.     Compt.  Rend.  Soc.  Biol.,  1898,  p.  103. 

Musser,  Sailer.     Philadelphia  Med.  Jour.,  1898,  p.  1408. 

Nonieviitch.     Baumgarten's  Jahresber.,  1897,  \).  415. 

Pairigeon.     Recherch.  s.  1.  nombre  d.  glob,  rouges.,  Paris,  1877. 

Pee.     Diss.  Berlin,  1890. 

Petruschky.     Zeit.  f.  Hygiene,  Bd.  17,  p.  59. 

Pfeiffer.     Deut.  med.  Woch.,  1893,  p.  816. 

Pothier.     Jour.  Amer.  Med.  Assoc,  Vol.  30,  p.  884. 

Quincke.     Virchow's  Archiv,  Bd.  54,  p.  537. 

Raskin.     Cent.  f.  Bact.,  1889,  pp.  286,  433. 

Beineri.     Zahlung  d.  Blutkorp,  etc 

Rieder.     '  Leucocytose.     ^Miinch.  med.  Woch.,  1892,  p.  511. 

Roscher.     Blut.  bei  septisch.  Fieber,  Diss.  Berlin,  1894. 

Rosenbach.     Microorg.  bei  Wundinfection,  Wiesbaden,  1884. 

Roux,  Lannois.     Rev.  de  Med.,  1890,  p.  1011. 

Sanger.     Deut.  med.  Woch.,  1889,  p.  148. 

Singer.     Aetiol.  d.  acut.  Gelenkrheumat. 

Siitmann.     Deut.  Archiv  f.  klin.  Med.,  Bd.  53,  p.  323. 

Spronek.     Semaine  Med.,  1898,  p.  393. 

Stem,  Hirscfder.     Wien.  med.  Presse,  1888,  p.  1102. 

Timofj'wsky.     Cent.  f.  Path.,  1895,  p.  108. 

Toenissen.     Inaug.  Diss.  Erlangen,  1881. 

'Turk.     Klin.  Blutuntersuchungen  Wien.,  1897. 

Vorbach.     Diss.  Wurzburg,  1895. 

Wright,  Smith.     Lancet,  1897,  I.,  p.  656. 

Zabolotny.     Compt.  Rend.  Soc.  Biol.,  1897,  p.  520. 


CHAPTER    XVI. 
SYPHILIS,  TUBERCULOSIS,  LEPEOSY. 

SYPHILIS. 

Very  accurate  conclusions  regarding  the  state  of  the  blood  in  syphilis 
were  reached  by  Becquerel  and  Rodier,  who  stated  that  a  moderate  grade 
of  anemia  was  to  be  found  in  the  great  majority  of  cases,  that  as  long 
as  the  disease  progressed  without  complications  the  blood  maintained  a 
high  or  normal  standard,  and  that  if  the  course  of  the  disease  was  pro- 
longed, there  was  a  loss  of  red  cells.  They  noted  also  that  the  abuse  of 
mercury  might  lead  to  the  same  changes.  The  resemblance  of  the  anemia 
of  syphilis  to  that  of  chlorosis  was  also  early  recognized,  especially  by 
Ricord,  and  this  belief  was  later  supported  by  analyses  of  the  blood 
by  Grassi,  Wilbouche witch,  Keyes,  Laache,  Malassez,^  Gaillard,  and 
others,  who  found  in  the  secondary  and  tertiary  stages  of  most  cases  a 
loss  of  red  cells  and  Hb.  Keyes  was  the  first  to  point  out  that  mer- 
cury in  small  doses,  while  curing  the  disease,  increases  the  red  cells. 

The  grade  of  anemia  observed  was  usually  moderate,  the  majority  of 
cases  showing  slight  loss  of  red  cells,  which  however  sometimes  fell  to 
3-4  millions.  The  Hb  was  usually  found  diminished  more  than  the 
cells,  especially  by  Lezius  who  claimed  that  the  only  essential  lesion  of 
the  blood  in  syphilis  is  a  loss  of  Hb.  Other  patients  appeared  to  have 
normal  blood,  and  Sorensen  in  20  cases  failed  to  detect  any  distinct 
anemia.  On  the  other  hand,  Muller  reported  cases  in  which  all  the 
typical  lesions  oi  pernicious  anemia  were  present,  and  in  one  of  his  cases 
the  red  cells  fell  to  428,100.  Other  such  cases  are  reported  by  Ponfick, 
Kjerner,  Klein,  Laache,  Fisischella  (cited  by  Dominici). 

It  was  thus  established  that  syphilis  in  some  stages  and  in  some 
patients  may  entirely  fail  to  reduce  the  red  cells,  while  in  others  grave 
pernicious  anemia  must  be  charged  to  its  action.  The  later  studies 
have  been  concerned  with  the  more  detailed  course  of  the  blood  changes 
in  the  disease,  and  have  been  contributed  principally  by  Anc,  Lezius, 
Bieganski,  Konried,  Rille,  Loos,  Justus,  and  Riess. 

From  these  contributions  it  appears  that  the  blood  suffers  in  a  some- 
what uniform  degree  in  the  several  stages  of  uncomplicated  syphilis, 
but  unfavorable  conditions  and  abuse  of  mercury  may  greatly  aggravate 
the  changes  observed. 

Primary  Stage. — During  the  first  four  to  seven  weeks  after  infec- 
tion the  red  cells  do  not  diminish  perceptibly  in  number  (Lezius, 
Konried,  et  al.)  unless  there  is  fever  or  some  other  disturbing  factor, 
when  a  moderate  decrease  may  be  noted  from  the  first  (Stoukovenkoff). 


294  SYPHILIS,    TUBERCULOSIS,  LEPROSY. 

No  doubt,  as  Hayem  says,  these  disturbing  factors  are  frequently 
present,  and  it  still  remains  uncertain  whether  syphilis  alone  affects 
the  number  of  red  cells  during  the  first  few  weeks.  The  majority  of 
observations  indicate  that  it  does  not,  but  Riess  came  to  a  contrary 
conclusion,  while  Bieganski  found  uniform  polycythemia  in  the  early 
stages  of  syphilis. 

The  Hb  is  almost  invariably  diminished  from  the  first,  a  loss  of 
15-30  percent  being  commonly  noted  before  the  appearance  of  second- 
aries.    (Konried.) 

Secondary  State. — There  is  uniform  agreement  among  very  numer- 
ous observers  that  with  the  outbreak  of  secondary  symptoms  the  red 
cells  begin  to  fall  rapidly,  reaching  in  untreated  cases  as  low  as  2 
millions  or  less.  (Konried.)  In  10  cases  Wilbouchewitch  found  an 
average  decrease  of  229,000  cells  daily.  At  the  same  time  the  Hb 
continues  to  diminish  and  may  fall  to  55-25  percent  within  a  few 
weeks  or  months.  Riess  denies  that  the  Hb  suffers  particularly  at  the 
outbreak  of  the  eruption.  With  the  appearance  of  fever  and  new 
eruptions  a  further  and  more  marked  loss  of  cells  and  Hb  has  been 
observed.  (Stoukovenkoff.)  Under  unfavorable  hygienic  conditions, 
and  in  feeble  and  especially  in  young  subjects,  the  anemia  in  this  stage 
may  be  unusually  severe.  In  untreated  cases  the  disappearance  of  the 
eruption  is  not  followed  by  any  immediate  improvement  in  the  blood. 

Tertiary  Stage. — In  untreated  cases  there  can  be  no  doubt  that  the 
anemia  may  progress  till  the  pernicious  type  is  established,  but  treat- 
ment usually  limits  the  impoverishment  of  the  blood  so  that  only 
moderate  grades  of  anemia  are  commonly  observed.  Konried  found 
an  average  of  4  million  red  cells  in  ten  cases,  and  from  50-80  percent 
of  Hb  in  22  cases  suffering  from  gummatous  lesions. 

In  several  cases  showing  advanced  tertiary  lesions  (gummata)  at 
autopsy  the  writer  has  found  different  grades  and  types  of  secondary 
chlorotic  and  pernicious  anemia.  In  one  the  spleen  was  much  enlarged 
and  contained  gummata,  while  the  blood  showed  the  lesion  of  secondary 
pernicious  anemia,  with  a  tendency  toward  the  microcytic  type,  and 
with  low  Hb-index.  In  other  cases  the  abundant  megalocytes  with 
increased  Hb  closely  resembled  those  of  primary  pernicious  anemia. 
It  is  especially  in  infants  that  syphilis  induces  the  grave  types  of 
anemia. 

Eifects  of  Mercury  Upon  the  Blood  in  Syphilis. — The  effect  of 
proper  doses  of  mercury  in  arresting  the  progress  of  the  anemia  of 
syphilis  was  clearly  stated  by  Wilbouchewitch,  who  reported  an  aver- 
age gain  of  102,000  cells  daily  in  10  cases,  while  Keyes  and  many 
later  observers  have  fully  verified  these  results.  That  prolonged  use 
of  mercury  may  of  itself  lead  to  marked  anemia  resembling  that  of 
syphilis  was  early  noted  by  Becquerel  and  Rodier,  and  was  also  dem- 
onstrated both  in  man  and  animals  by  Wilbouchewitch,  and  later  by 
Bieganski,  Hayem,  Lezius,  Anc,  Schlesiuger,  and  Jelleneff.  The  ex- 
tent to  which  mercurial  treatment  may  be  carried  without  diminishing 
the  red  cells  or  Hb  has  been  placed  at  24  days,  by  Gaillard ;  at  25-35 


I 


JUSTUS'    TEST  IN  THE  BLOOD   OF  SYPHILIS.  295 

inunctions,  by  Konried  ;  at  16  injections  (gram  .5,  1  percent  Hg-ben- 
zoate)  by  Jelleneff ;  and  at  140—150  milligrams  of  bichloride,  or  77 
milligrams  of  benzoate,  injected  in  increasing  doses,  by  Lindstrom. 

Daring  this  period  most  observers  agree  that  both  red  cells  and  Hb 
increase  from  the  first,  and  many  instances  of  moderate  polycythemia 
are  recorded.  At  the  same  time  the  eruption  commonly  disappears. 
If  treatment  is  continued  beyond  this  point,  especially  if  the  patient  is 
salivated,  the  cells  and  Hb  steadily  and  sometimes  rapidly  decline  and 
well-marked  mercurial  anemia  is  established.  Jawein,  however,  failed 
to  observe  any  anemia  during  prolonged  courses  of  inunctions. 

The  Leucocytes  in  Syphilis. — Leucocytosis  was  early  observed  in 
syphilis  and  its  usual  connection  with  the  hyperplasia  of  lymph  nodes 
was  one  of  the  facts  that  led  Virchow  to  locate  the  origin  of  the 
lymphocytes  in  these  structures.  More  detailed  study  of  the  behavior 
of  the  leucocytes  was  made  by  Wilbouchewitch,  Biganski,  JelleneflP, 
Konried,  and  Rille,  who  have  shown  that  the  leucocytosis  of  syphilis 
is  connected  principally  with  the  eruptions  and-  the  anemia  of  the 
disease. 

In  the  primary  stage,  before  the  appearance  of  the  eruption,  the 
leucocytes  are  usually  normal  (Rille),  but  Jelleneif  found  that  an  in- 
crease of  white  cells  usually  precedes  the  development  of  anemia,  and 
Konried's  cases  showed  a  slight  leucocytosis  (maximum  16,400)  in  the 
first  weeks  of  the  primary  stage. 

In  the  secondary  stage,  with  the  appearance  of  eruptions,  anemia, 
and  hyperplasia  of  lymph  nodes,  the  leucocytes  are  nearly  always  in- 
creased. In  Konried's  cases  of  untreated,  secondary  syphilis  the  white 
cells  were  never  under  10,000,  while  the  maximum  figure  was  17,500. 
Riess,  however,  found  leucocytosis  absent  in  many  cases,  but  observed 
an  increase  to  20,000  in  some  instances,  while  the  excess  of  lympho- 
cytes was  usually  very  distinct  (maximum  68  percent).  The  adminis- 
tration of  mercury  commonly  reduces  the  white  cells,  which  become 
normal  with  the  disappearance  of  the  eruption  and  the  anemia.  Jel- 
leneif found  the  leucocytosis  to  be  more  nearly  proportionate  to  the 
extent  of  the  eruption  than  to  the  size  of  the  lymph  nodes,  and  noted 
leucocytosis  in  the  absence  of  external  signs  of  lymphoid  hyperplasia. 

The  increase  affects  principally  the  small  and  large  lymphocytes, 
but  the  eosinophile  cells  may  also  be  increased,  especially  in  those 
cases  with  marked  papular  exanthems.  (Rille.)  Zappert  found  a  slight 
increase  of  eosins,  4.91  percent  in  one  early  case,  but  normal  numbers 
in  seven  others.  The  proportion  of  lymphocytes  diminishes  as  the 
patient  improves,  falling  after  each  inunction.  (Riess.)  In  very  se- 
vere cases  there  may  be  progressive  polynuclear  leucocytosis.  Myelo- 
cytes have  been  found  by  Rille  and  others  in  both  secondary  and 
tertiary  syphilis. 

In  tertiary  stages  with  gummatous  lesions  the  leucocytosis  usually 
persists,  but  lymphocytosis,  though  sometimes  distinct,  is  less  constant. 
Konried  found  8,500-17,710  leucocytes  in  nine  cases. 

Justus'  Test  in  the  Blood  of  Syphilis. — By  a  series  of  observations 


296 


SYPHILIS,    TUBERCULOSIS,   LEPROSY. 


in  over  300  cases  Justus  came  to  the  conclusion  that  in  the  blood  of 
florid  syphilis  after  injections  of  moderate  doses  of  various  preparations 
of  mercury,  or  after  inunctions,  there  is-  a  period  of  a  few  hours  or 
days  during  which  the  Hb  is  considerably  reduced  (10-20  percent). 
After  a  certain  period,  varying  with  the  general  condition  of  the  pa- 
tient and  the  severity  of  the  symptoms,  the  Hb  begins  to  increase.  In 
some  cases  the  diminution  continued  only  one  day  and  in  others  it  was 
repeated  after  each  of  three  or  four  injections.  The  reaction  was  noted 
in  all  stages  of  the  disease  after  the  primary  swelling  of  lymph  nodes, 

Fig.  23. 


XI 

XII 

16    1 

18 

19 

20 

21 

22 

23 

24 

25    2 

5   27 

28 

29 

30 

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2 

3 

4 

5 

6 

7 

8 

9 

10 

11 

12 

13 

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15 



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y 

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HB.  Je90 

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Course  of  changes  in  Hb  in  Justus'  test. 


(Roman  numerals  indicate  intravenous  injections  of  sub- 
limate.) 


and   in   hereditary  syphilis,   but  could  not    be   obtained   "  during  or 
shortly  before  the  symptoms  of  the  disease  begin  to  disappear." 

In  the  serum,  within  two  minutes  after  the  intravenous  injection  of 
bichloride,  Justus  found  the  spectrum  of  oxyhemoglobin.  In  blood 
smears  immediately  after  the  injection  many  pale  degenerating  red 
cells  were  found,  which  disappeared  within  a  few  minutes.  It  thus 
appeared  that  the  mercury  had  caused  an  immediate  solution  of  red 
cells  in  the  plasma.  The  specific  gravity  of  the  blood  M'as  not  studied 
except  in  one  case  in  which  it  showed  irregular  fluctuations. 


CONGENITAL  SYPHILIS.  297 

The  value  of  Justus'  test  has  not  been  fully  determined. 

Cabot  reported  positive  results  iu  seven  cases  of  syphilis  and  negative  in 
32  control  cases,  but  obtained  a  positive  reaction  in  a  case  of  chlorosis. 

Jones  recently  applied  the  test  in  35  cases  of  syphilis  in  various  stages,  and 
in  18  controls,  estimating  the  Hb  usually  by  the  specific  gravity  method.  None 
of  the  control  cases  responded  to  the  test.  Of  17  cases  of  secondary  syphilis 
13  responded,  and  four  failed.  Of  eight  cases  of  chancre  with  adenitis,  two 
responded  to  the  test  by  Fleischl's  method,  but  failed  when  tested  by  the 
specific  gravity  method.  Six  others  Avere  not  tested  by  Fleischl's  instrument. 
The  conclusion  was  reached  that  a  positive  reaction  has  considerable  diag- 
nostic value,  while  a  negative  result  is  of  less  significance.  Jones'  conclu- 
sions would  be  more  reliable  had  he  used  the  Fleischl  instrument  through- 
out. 

Further  studies  are  required  before  the  value  of  Justus'  test  can  be 
shown,  but  on  general  grounds  it  would  seem  that  the  test  v^ould  prove 
unreliable  in  many  forms  of  anemia,  when  the  globulicidal  action  of 
mercury  might  dissolve  red  cells. 

CONGENITAL    SYPHILIS. 

Syphilitic  infants  invariably  suffer  from  anemia.  In  the  mildest 
cases,  Loos  found  over  5  million  red  cells  and  65-75  percent  of  Hb. 
Schiff  also  found  the  usual  polycythemia  of  infants  in  mild  cases  of 
congenital  syphilis.  In  the  majority  of  cases  there  is  considerable 
loss  of  red  cells  and  the  Hb  falls  to  a  low  figure,  minimum  21  percent. 
(Loos.)  In  the  severer  forms  the  blood  may  show  the  changes  of  sec- 
ondary or  progressive  pernicious  anemia,  examples  of  which  have  been 
described  by  Loos,  Luzet,  Monti,  Berggrun,  and  others. 

Whatever  the  grade  of  anemia,  the  changes  are  influenced  by  the 
special  tendencies  of  infants'  blood.  Marked  differences  in  the  size 
of  the  cells  are  early  established,  nucleated  red  cells  are  frequently 
seen  in  abundance,  and  white  cells,  especially  lymphocytes,  are  often 
present  in  greatly  increased  numbers.  Loos  noted  an  extreme  degree 
of  polychromasia  in  the  large  nucleated  red  cells  in  congenital  syphilis. 
The  leucocytes  did  not  fall  below  12,000  in  any  of  Loos'  16  cases,  and 
in  one  fatal  case  rose  to  58,000.  Baginsky,  and  Monti  and  Berggrun 
have  also  reported  excessive  leucocytosis  in  similar  cases,  while  the 
former  author  speaks  of  a  distinct  leukemic  tendency  to  be  found  in 
the  blood  of  congenital  syphilis. 

The  lymphocytes  usually  fall  Avithin  normal  limits  for  this  age. 
Eosinophile  cells  are  sometimes  increased,  especially  when  the  eruption 
is  extensive.  (Loos.)  The  presence  of  a  few  myelocytes  in  the  severe 
cases  makes  the  resemblance  of  these  cases  of  syphilitic  anemia  to  v. 
Jaksch's  anemia  often  very  close,  while  the  excess  of  large  lymphocytes 
may  lead  to  confusion  of  the  disease  with  lymphatic  leukemia  of 
Frankel's  type. 

Congenital  syphilis  is  recognized  by  Demelin,  as  one  of  the  common 
causes  of  melena  neonatorum.  In  such  a  case,  dying  four  days  after 
birth  from  abdominal  hemorrhage,  the  writer  found  in  the  blood  the 
typical  characters  of  idiopathic  pernicious  anemia,  especially  in  the 


298  SYPHILIS,    TUBERCULOSIS,    LEPROSY. 

large  number  of  raegaloblasts.     The  marrow  was  everywhere  lymphoid, 
and  showed  pronounced  megaloblastic  changes. 

TUBERCULOSIS. 

The  fact  that  the  blood  of  consumptives  may  often  fail  to  show  any 
changes  comparable  with  the  pallor  of  the  skin  and  the  emaciation  of 
these  subjects  was  noted  in  the  first  studies  of  the  blood  by  Andral  and 
Gavarret,  Becquerel  and  Rodier,  and  others.  The  discrepancy  between 
blood  and  facial  appearance  was  fully  recognized  by  Laache  who,  find- 
ing an  average  of  4.4  million  cells  in  14  cases,  stated  that  phthisis  of 
itself  usually  does  not  tend  toward  marked  anemia.  Similar  results  in 
the  hands  of  Sorensen,  Oppenheimer,  Gnezda,  Barbacci,  and  Reinert, 
confirmed  this  opinion  in  a  considerable  group  of  cases,  although  well- 
marked  chlorotic  anemia  was  occasionally  encountered.  In  the  Massa- 
chusetts General  Hospital  series,  Cabot  found  41  out  of  60  patients 
with  more  than  4  million  red  cells,  and  69  of  80  cases  with  more  than 
50  percent  of  Hb. 

Yet  Malassez  had  in  1874  reported  well-marked  anemia  in  some 
early  cases,  had  seen  the  red  cells  fall  over  half  a  million  in  the  course 
of  one  week,  and  found  less  than  a  million  cells  in  an  advanced  case 
with  diarrhea.  In  nearly  all  of  their  series  of  cases  Laker  and  Feno- 
glio  found  low  percentages  of  Hb,  and  the  specific  gravity  was  found 
markedly  reduced  by  Schmaltz  and  Peiper. 

In  1893  current  views  were  presented  by  v.  Noorden  who  stated 
that  in  pulmonary  tuberculosis  a  loss  of  more  than  20  percent  of  red 
cells  or  Hb  is  seldom  observed  unless  from  complications  such  as  hem- 
orrhage, suppuration,  or  amyloid  degeneration. 

The  subject  was  at  this  time  thoroughly  reviewed  by  Grawitz '  and 
Strauer,  who  found  three  distinct  periods  in  the  changes  of  the  blood 
in  phthisis. 

1.  With  beginning  apical  lesions,  they  generally  found  marked 
chlorotic  anemia  with  loss  of  red  cells,  irregular  leucocytosis,  and  reduc- 
tion in  dry  residue  and  specific  gravity.  In  robust  subjects  however 
the  blood  during  this  stage  was  sometimes  normal. 

2.  In  pale  emaciated  subjects  with  chronic  phthisis  and  cavities,  but 
without  much  fever,  the  blood  commonly  did  not  vary  from  the  normal 
standard,  the  red  cells  numbering  5  millions  or  more,  the  leucocytes 
5,000-10,000,  the  dry  residue  of  blood  and  serum  being  moderately 
low,  but  the  specific  gravity  higher  than  the  dry  residue  would  indicate. 

3.  When  hectic  fever  supervened,  usually  from  suppuration  in  cavi- 
ties, and  the  patient  began  to  suffer  from  septicemia,  the  blood  became 
rapidly  impoverished,  the  red  cells  were  then  much  reduced,  the 
leucocytes  frequently  much  increased,  and  the  dry  residue  and  specific 
gravity  falling  to  a  low  point. 

The  intense  septicemia  of  rapidly  advancing  phthisis  was  found  to 
yield  some  very  severe  grades  of  anemia,  in  one  of  which  the  red  cells 
fell  to  700,000.     Similar  cases  have  been  reported  by  Malassez  ^  and 


TUBERCULOSIS.  299 

Limbeck/  both  of  which  suffered  from  marked  diarrhea.  In  Lim- 
beck's case  there  was  also  tuberculous  peritonitis,  and  the  blood  showed 
marked  poikilocytosis  and  increased  Hb-index. 

In  the  attempt  to  correlate  his  own  and  Robert's  divergent  results  Dehio 
described  two  different  types  of  the  disease,  the  marantic  and  the  anemic 
cases.  In  the  former  group  the  patients  showed  a  marked  tendency  to 
emaciate  while  their  blood  retained  a  good  standard,  while  in  the  others 
all  grades  of  chlorotic  anemia  might  be  observed. 

It  would  seem  that  the  classifications  of  both  Dehio  and  Grawitz 
are  based  on  accurate  clinical  study.  The  following  conclusions  may 
be  drawn  regarding  the  general  course  of  blood  changes  in  tubercu- 
losis. 

1.  The  primari/  anemia  of  tuberculosis  is  seen  not  only  in  diseases 
of  the  lungs  but  quite  as  frequently  in  chronic  tuberculosis  of  other 
tissues,  especially  of  the  lymph  nodes  and  bones,  constituting  the  very 
numerous  group  of  cases  of  ''  lymphatic  anemia."  Moreover,  it  has 
recently  been  placed  beyond  doubt  that  the  chronic  anemia  of  Hodg- 
kin's  disease  is  in  a  large  proportion  of  cases  the  result  of  tuberculosis 
of  lymph  nodes. 

The  peculiar  character  of  these  cases  of  secondary  tuberculous  ane- 
mia has  been  described  by  Laker,  Neubert,  Wiskeman,  Vierordt,  Bier- 
freund.  Brown,  Dane,  and  many  others,  and  they  constitute  one  of  the 
largest  groups  of  cases  encountered  in  routine  blood  examinations. 
In  appearance  the  patients  clearly  resemble  cases  of  chlorosis  and  the 
blood  shows  a  slightly  or  considerably  reduced  number  of  red  cells, 
more  marked  loss  of  Hb,  and  usually  slight  relative  or  absolute  lym- 
phocytosis. Yet  this  description  does  not  apply  to  all  cases  of  early 
tuberculosis  or  phthisis,  as  some  of  them  from  the  first  appear  anemic 
and  yet  show  normal  cells  and  Hb. 

2.  The  second  group  in  ivhich  the  blood  is  but  slightly  altered  in  quality, 
although  cavities  have  formed  in  the  lungs  and  the  patient  is  pale  and 
emaciated,  includes  the  majority  of  cases  of  chronic  phthisis.  One  of 
the  most  striking  examples  seen  by  the  writer  occurred  in  a  patient 
suflPering  from  subacute  tuberculous  empyema  from  which  the  pus 
contained  very  large  numbers  of  tubercle  bacilli.  But  the  same  qual- 
ity of  blood  is  sometimes  seen  with  early  apical  lesions  and  moderate 
emaciation,  while  considerable  anemia  may  exist  in  moderately  ad- 
vanced cases  of  phthisis  who  are  not  suifering  from  distinct  hectic  fever. 

The  cause  of  the  concentration  of  the  blood,  or  oligemia,  in  the 
average  phthisical  subject,  for  such  must  be  the  condition,  is  probably 
to  be  found,  as  indicated  by  Heidenhain,  Gartner  and  Romer,  and 
Grawitz,^  in  the  specific  lymphogogic  action  of  the  toxines  of  the 
tubercle  bacillus,  by  which  there  is  established  a  continuous  excess  in 
the  balance  of  fluids  which  leave  the  tissues  through  the  lymphatics. 
This  view  is  strongly  supported  by  the  resemblance  which  exists  be- 
tween the  tuberculous  and  the  typhoidal  processes,  both  showing  a  pe- 
culiar relation  to  lymphatic  structures  and  both  tending  to  concentrate 
the  blood.  Identical  effects  upon  the  blood  follow  also  the  experi- 
mental injection  of  tuberculin  and  typho-toxin. 


300  SYPHILIS,    TUBERCULOSIS,   LEPROSY. 

By  this  means  the  considerable  destruction  of  blood  which  results 
from  the  chronic  toxemia,  hemorrhages,  and  malnutrition  of  the  dis- 
ease, is  obscured,  and  only  becomes  visible  at  autopsies  on  these  sub- 
jects when  the  shrunken  appearance  of  the  tissues  finds  a  parallel  in 
the  diminished  total  volume  of  blood  which  is  often  apparent  to  the 
naked  eye.  In  the  inajority  of  cases  of  well-advanced  phthisis,  therefore, 
approximately  normal  blood  indicates  considerable  absorption  of  the  tox- 
ines  of  the  tubercle  bacillus.  Prolonged  and  profuse  night  sweats,  and 
severe  diarrhea,  doubtless  have  a  similar  effect,  which,  however,  is 
usually  overbalanced  by  the  destruction  of  blood  which  results  from 
the  associated  septicemia.  Normal  blood  is  found  in  many  phthisical 
patients  who  do  not  sweat  or  suffer  from  diarrhea.  Yet  in  some  ex- 
treme cases  one  or  both  of  these  factors  may  very  well  prove  to  be  the 
chief  influence  in  the  concentration  of  the  blood. 

3.  The  third  group  of  cases  includes  those  who  are  anemic  from  the 
first  or  who  become  anemic  in  the  terminal  stage  of  the  disease,  in 
either  instance  from  the  destruction  of  blood  which  occurs  in  all  se- 
vere septicemias.  Since  the  severe  hectic  fever  of  phthisis  is  largely 
referable  to  mixed  infection,  the  condition  established  is  not  very  dif- 
ferent from  the  ordinary  type  of  pyogenic  sepsis.  The  destruction  of 
cells  may  be  quite  rapid.  Malassez  observed  losses  of  730,000  cells 
in  one  month,  and  760,000  in  three  weeks  in  cases  without  hemor- 
rhage. Here  belong  the  acute  cases  with  grave  anemia  described  by 
Malassez,  Limbeck,  and  Grawitz,  from  which  it  appears  that  the  blood 
in  tuberculosis  may  develop  much  the  same  characters  as  in  pernicious 
anemia. 

Effects  of  Complications. — Hemoptysis  causes  impoverishment  of 
the  blood  in  proportion  to  the  extent  of  the  hemorrhage.  Malassez 
observed  a  reduction  of  940,000  cells  from  small  hemorrhages  in  a 
period  of  eight  days.  Amyloid  degeneration  is  seen  with  advanced  and 
anemic  cases,  but  its  effects  on  the  blood  have  not  been  specially 
studied.  Stenosis  of  the  larynx,  and  diabetes,  have  been  found  with 
concentrated  blood.     (Grawitz.) 

Regeneration  of  the  Blood  in  Phthisis. — Prompt  regeneration  of 
the  blood  after  hemoptyses  has  been  observed  by  Malassez,  but  such 
improvement  must  depend  largely  upon  the  general  condition  of  the 
patient.  Laker  came  to  the  conclusion  that  if  the  Hb  did  not  steadily 
improve  after  operation  on  tuberculous  foci,  it  might  safely  be  con- 
cluded that  all  of  the  disease  had  not  been  removed.  In  seven  of 
Bierfreund's  cases  and  in  two  of  Brown's,  this  rule  held  good,  and  three 
times  a  steady  decline  in  Hb  preceded  for  several  weeks  the  develop- 
ment of  symptoms  of  general  tuberculosis  {vide  infra). 

In  phthisis,  as  well  as  in  other  tuberculous  processes,  great  caution  must 
be  used  in  judging  of  the  patient's  impi'ovement  from  an  increase  in  red 
cells  or  Hb.  The  writer  has  seen  the  Hb  and  red  cells  increase  while 
the  patient  teas  rapidly  losing  flesh,  the  lesions  advancing,  and  the 
total  quantity  of  blood  doubtless  falling.  In  several  of  Bierfreund's 
tases  the  Hb  steadily  increased  while  the  patient  was  developing  general 
cuberculosis. 


THE  LEUCOCYTES  IN  TUBERCULOSIS.  301 

Morphological  change.'',  in  the  red  cells  are  rather  less  marked  than 
in  most  other  types  of  secondary  anemia,  owing  probably  to  the  con- 
servative eiFect  of  a  plasma  of  high  gravity.  When  anemia  exists  it  is 
usually  of  the  simple  chlorotic  type  with  relatively  high  Hb-index. 
In  his  case  of  grave  anemia  Limbeck  described  extreme  poikilocytosis, 
but  nucleated  red  cells  were  apparently  absent.  In  two  very  anemic 
acute  cases  lasting  4  and  5  weeks,  the  writer  found  under  two  million 
red  cells,  but  there  were  no  distinct  megalocytes  and  no  nucleated  red 
cells.  Cabot  finds  that  nucleated  red  cells  are  usually  absent  in 
tuberculosis,  even  after  hemorrhage,  and  contrasts  this  fact  with  their 
abundance  in  carcinoma.  Degenerative  changes  in  the  red  cells  in 
tuberculosis  are  not  marked.  In  13  cases  of  uncomplicated  phthisis 
Grawitz^  found  no  signs  of  granular  degeneration. 

The  Leucocytes  in  Tuberculosis. — In  the  majority  of  cases 
of  uncomplicated  tuberculosis  the  leucocytes  remain  within  normal 
limits  or  are  distinctly  deficient  in  number.  This  rule  has  been  es- 
tablished principally  by  later  observers,  since  the  earlier  studies  cited 
by  Rieder,  Reinert,  and  others,  indicated  that  tuberculous  inflammation 
usually  excites  leucocytosis. 

Yet  Halla  noted  that  leucocytosis  was  usually  found  only  in  ad- 
vanced cases  with  fever,  and  Rieder  distinguished  the  fresh  cases  from 
chronic  febrile  tuberculosis  by  the  absence  of  any  increase  of  white 
cells  in  the  former.  It  is  perhaps  a  still  more  uniform  rule  that  leuco- 
cytosis is  found  almost  exclusively  in  the  febrile  and  anemic  cases,  but 
it  is  absent  also  in  many  febrile  periods. 

In  pulmonary  tuberculosis,  an  increase  of  leucocytes  is  usually  re- 
ferable to  suppurating  cavities,  advancing  pneumonia,  severe  anemia,  or 
hemoptysis.  Suppurating  cavities,  when  of  recent  formation,  usually 
raise  the  leucocytes  distinctly,  15,000  cells  being  frequently  seen,  and 
when  the  lung  is  softening  the  excess  may  be  much  greater.  The 
leucocytosis  usually  persists  while  the  fever  continues.  With  old 
cavities  the  expectoration  may  be  abundant,  but  the  leucocytes  usually 
fall  to  normal. 

In  the  pneumonia  of  various  types  which  complicates  phthisis,  the 
leucocytes  are  usually  much  increased,  but  considerable  areas  of  diifuse 
tuberculous  pneumonia  may  be  found  with  acute  miliary  tuberculosis, 
which  have  failed  to  increase  the  leucocytes  during  life.  A  lobar  pneu- 
monia causes  the  usual  leucocytosis,  but  the  writer  has  seen  both  lungs 
consolidated  and  riddled  with  small  cavities,  in  a  case  lasting  five  weeks, 
yet  the  leucocytes  were  never  found  above  12,000.  Tixe  absence  of  leuco- 
cytosis in  these  cases  of  acute  phthisis  which  resemble  pneumonia  may  often 
be  of  value  in  diagnosis.  Similarly  in  a  case  of  subacute  empyema  in 
which  the  tubercle  bacillus  was  largely  concerned,  the  leucocytes  were 
found  not  to  exceed  14,000  during  an  acute  febrile  period. 

The  leucocytosis  of  tuberculous  cachexia  is  moderate,  usually  between 
10,000  and  15,000.  After  hemoptysis  the  leucocytes  are  increased  in 
proportion  to  the  hemorrhage,  but  the  increase  is  transient. 

Acute  general  miliary  tuberculosis  offers  the  best  illustration  of  the 


302  SYPHILIS,    TUBERCULOSIS,    LEPROSY. 

failure  of  pure  tuberculous  inflammation  to  induce  leucocytosis.  Rieder, 
Limbeck,  Warthin,  and  Cabot  find  rather  a  diminution  of  leucocytes, 
often  to  an  extreme  degree  and,  as  Warthin  has  shown,  during  a  pro- 
lono-ed  period.  Minor  suppurative  complications  seem  to  have  no 
capacity  to  raise  the  white  cells,  but  in  some  reported  cases  a  high  per- 
centage of  polynuclear  cells  was  noted  among  the  scanty  leucocytes. 
(Warthin.) 

Tuberculous  inflammations  of  serous  membranes,  when  uncompli- 
cated by  pyogenic  infection,  follow  the  type  of  pure  tuberculous  in- 
flammation elsewhere  and  fail  to  increase  the  leucocytes.  In  many 
cases  however  there  appears  to  be  mixed  infection,  and  the  eifusion,  in- 
stead of  remaining  serous  or  sero-sanguinolent,  becomes  sero-purulent 
and  purulent.  In  such  cases  of  pleurisy  with  sero-purulent  or  puru- 
lent exudate  the  writer  has  found  a  moderate  increase  of  leucocytes, 
usually  in  proportion  to  the  height  of  the  temperature.  While  it  is 
undoubtedly  true  that  the  tubercle  bacillus  may  of  itself  produce  pus 
the  fact  remains  that  it  is  seldom  or  never  seen  alone  in  purulent  exu- 
dates. The  slight  leucocytosis  that  accompanies  cases  of  purulent  tu- 
berculous inflammations  of  serous  membranes  is  perhaps  a  further  in- 
dication that  these  cases  represent  mixed  infections. 

Tuberculous  Meningitis. — In  the  majority  of  reported  cases  of  this 
important  localization  of  the  disease  leucocytosis  has  been  absent,  as 
seen  by  Limbeck,^  Pick,  Rieder,  Sorensen.  Yet  in  five  of  7  cases 
reported  by  Cabot  and  in  one  by  Ziemke,  there  was  distinct  leucocy- 
tosis, from  14,700-34,300,  while  in  one  of  Rieder's  cases  there  were 
14,400  white  cells.  It  is  difficult  to  reconcile  these  conflicting  results. 
Some  of  the  leucocytoses  may  have  been  ante-mortem  phenomena,  but 
not  all.  Ziemke's  case  was  one  of  advanced  general  tuberculosis.  The 
writer  has  seen  cases  with  leucocytosis,  but  complicating  terminal  pneu- 
monia was  in  each  instance  found  at  autopsy. 

Morphology  of  Leucocytes  in  Tuberculosis. — In  most  cases  of  chronic 
tuberculosis,  when  the  leucocytes  are  normal  or  diminished,  the  mono- 
nuclear cells  are  relatively  in  excess,  but  in  some  instances  the  usual 
rule  is  reversed,  as  in  Warthin's  case,  and  the  polynuclear  cells  are  in 
excess.  Distinct  lymphocytosis  is  seen  in  many  chronic  cases,  espe- 
cially those  with  large  lymph  nodes  (lymphatic  anemia).  Lymphatic 
leukemia  sometimes  develops  in  tuberculous  subjects,  but  the  relation  of 
the  two  diseases  is  uncertain.  When  distinct  leucocytosis  occurs,  excess 
of  polynuclear  cells  is  usual,  and  pyogenic  infections,  etc.,  are  indicated. 

Neusser  believes  that  eosinophilia  indicates  relative  immunity  to  tuber- 
culosis. General  experience  seems  to  show  tbat  eosins  are  frequently  pres- 
ent, usually  in  normal  numbers,  in  the  blood  in  chronic  tuberculosis,  and 
sometimes  absent  in  the  acute  cases,  or  when  there  is  fever  and  leucocytosis. 
Zappert  found  none  in  2  of  5  cases  of  febrile  tuberculosis.  They  are  com- 
monly increased,  sometimes  to  an  extreme  degree,  in  the  afebrile  period  fol- 
lowing injections  of  tuberculin.     (Zappert.) 

Tuberculosis  of  Bones  and  Joints. — Valuable  studies  in  this  field 
have  been  contributed  by  Brown  in  72,  and  Dane  in  41  cases,  of  tuber- 
culosis of  hip  and  spine. 


BACTERIOLOGICAL  EXAMINATION  OF  THE  BLOOD.  303 

From  these  studies  it  appears  that  the  above  conditions  are  very 
frequently  accompanied  by  moderate  or  marked  leucocytosis  (maximum 
41,000),  which  is  usually  referable  to  secondary  infection  and  the  for- 
mation of  pus.  Yet  Brown  observed  several  cases  with  leucocytosis 
but  without  formation  of  abscess,  and  believes  that  leucocytosis  may 
be  referable  alone  to  increased  activity  of  the  tuberculous  process.  A 
frequent  cause  of  leucocytosis,  often  of  marked  degree,  was  secondary 
infection  of  the  sinus  after  operation.  The  leucocytosis  was  usually 
but  not  always  associated  with  fever.  Both  authors  agreed  that  when 
leucocytosis  was  absent  in  cases  with  abscess,  secondary  infection  had 
not  occurred,  since  the  pus  was  sterile.  They  did  not  apparentl}^  con- 
sider the  possibility  that  a  micro-organism  once  present  may  disappear, 
or  that  leucocytosis  may  disappear  when  pus  ceases  to  form. 

Myelocytes  have  been  reported  in  scanty  numbers  in  a  few  cases. 

Chemistry. — Specal  chemical  alterations  of  the  blood  in  tubercu- 
losis have  not  been  demonstrated,  but  the  usual  changes  of  secondary 
anemia  have  been  reported  in  a  few  cases.  Hammarschlag  found  a  low 
gravity  only  in  cachectic  cases.  Moderate  reductions  only  were  ob- 
served by  Devoto  and  Scholkoff,  but  Schmaltz  found  a  gravity  of  1.036 
in  an  advanced  case  of  phthisis,  and  Grawitz's  case  of  grave  anemia 
gave  1.032. 

The  gravity  is  much  lower,  in  proportion  to  the  loss  of  cells,  than  in 
pernicious  anemia.  Dieballa  found  a  density  of  1.039  in  a  case  of 
phthisis  with  2.4  million  cells,  and  in  one  of  pernicious  anemia  with 
only  840,000  cells. 

Freund  found  in  the  blood  of  tuberculous  subjects  a  body  which  he 
regarded  as  cellulose,  which  Nischimura  has  likewise  identified,  while 
others  have  found  the  same  substance  in  tuberculous  tissues. 

Bacteriological  Examination  of  the  Blood  in  Tuberculosis. — 
Even  before  the  discovery  of  the  tubercle  bacillus  Weigert  had 
pointed  out  the  considerable  involvement  which  the  vessels  may  show 
in  acute  miliary  tuberculosis.  Weichselbaum,  in  1884,  was  able  with 
prolonged  searching  to  find  numbers  of  tubercle  bacilli  in  stained 
specimens  of  the  clotted  blood  of  the  great  vessels  in  three  cases  of 
acute  general  tuberculosis.  In  the  same  year  Meisels  and  Lustig  both 
succeeded  in  finding  tubercle  bacilli  in  the  blood  intra  vitam,  the  speci- 
mens having  been  squeezed  from  the  finger  tip  during  a  period  of  ris- 
ing pyrexia.  In  the  blood  of  the  spleen  the  bacilli  were  much  more 
numerous  and  Meisels  recommended  aspiration  of  the  spleen  as  an  aid 
in  the  diagywsis  of  obscure  cases.  Rutiraeyer  also  succeeded  in  finding 
many  bacilli  in  the  aspirated  splenic  blood  of  one  of  two  cases  examined 
shortly  before  death.  In  a  case  which  eventually  recovered.  Sticker, 
after  considerable  search,  found  a  few  bacilli  in  the  finger  blood  taken 
on  the  tenth  day  of  the  illness. 

With  the  introduction  of  tuherculin,  Liebmann  claimed  to  have  found 
tubercle  bacilli  in  56  of  141  blood  specimens,  most  abundantly  about  24 
hours  after  the  injection  of  tuberculin.  Grave  doubt  was,  however,  thrown 
upon  all  previous  work  in  this  field  by  the  negative  results  obtained  by  Gutt- 


304  SYPHILIS,    TUBERCULOSIS,    LEPROSY. 

mann  and  by  Kossel,  who  called  attention  to  the  danger  of  contamination 
in  such  specimens.  This  method  of  diagnosis  has  not  been  followed  up  in 
later  years,  although  Kronig,  in  1894,  recommended  the  staining  of  centri- 
fugedlaked  blood  in  doubtful  cases  of  miliary  tuberculosis. 

In  the  blood  of  tuberculous  cadavers  various  micro-organisms  have 
been  isolated  by  Pasquale,  Petruschky,  Canon,  Welch  and  Nuttall, 
and  others.  Cultures  of  the  blood  during  life  have  been  made,  by 
reliable  methods,  by  Sittmann,  Kraus,  Kuhnau,  Hewelke,  White,  Mich- 
aelis  and  Meyer,  and  Hirschlaif. 

Of  their  79  cases  of  advanced  and  usually  febrile  phthisis,  there 
were  23  positive  and  56  negative  results.  Staphylococcus  pyogenes  aur- 
eus or  albus  was  isolated  in  20  cases.  Streptococcus  pyogenes  and  a  diplo- 
coccus  in  1  case  each,  and  the  tubercle  bacillus  was  once  obtained  from 
inoculation,  by  Kuhnau.  The  pyogenic  germs  were  sometimes  found 
together.  Jakowsky  and  Petruschky  were  rather  more  successful, 
drawing  the  blood  through  the  skin,  but  this  method  is  unreliable. 

There  can  be  little  doubt  therefore  that  the  blood  in  the  late  stages 
of  phthisis  suffers  bacterial  invasion  as  in  other  forms  of  septicemia. 
Kuhnau's  one  positive  result  from  12  inoculations  of  the  blood  of  se- 
vere febrile  cases  does  not  encourage  further  search  for  the  tubercle 
bacillus  in  the  blood  of  tuberculous  subjects. 

LEPROSY. 

^^Winiarski,  in  1892,  studied  the  blood  in  17  cases  illustrating  various 
phases  of  this  disease.  ,In  some  cases  he  found  polycythemia,  6.38- 
6.09  million  red  cells,  which  may  perhaps  be  referred  to  local  stasis, 
as  the  hands  appeared  cyanosed.  Few  of  the  patients  showed  any 
marked  loss  of  cells,  the  average  being  5.05  millions  for  9  men,  and 
4.3  millions  for  8  women.  Winiarski  therefore  concluded  that  the 
milder  cases  of  one  or  two  years'  standing  do  not  suffer  from  any  dis- 
tinct anemia.  Yet  in  2  advanced  cases  with  extensive  lesions,  the  red 
cells  numbered  2.3  and  1.9  millions,  and  the  latter  patient  presented 
many  signs  of  pernicious  anemia.  In  these  cases  the  anemia  was  re- 
ferred to  extensive  ulceration.  The  Hb  suffered  even  less  than  the 
cells,  usually  registering  80-118  percent  in  all  but  the  two  very 
anemic  cases.  The  Hb-index  was  uniformly  high,  and  in  one  case 
with  1.9  million  cells  and  64  percent  Hb,  the  index  reached  1.7.  An 
increased  diameter  of  the  red  cells  was  noted  in  this  and  other  cases. 
The  leucocytes  were  normal  or  subnormal  in  number,  and  the  lympho- 
cytes were  in  relative  excess  (maximum  47  percent),  except  when  sup- 
puration occurred. 

Brown,  more  recently,  reported  his  observations  in  16  cases,  8  of 
which  appeared  to  be  quiescent  and  presented  normal  blood,  while  only 
one  showed  severe  anemia.  He  claimed  to  have  found  the  bacillus  in 
the  leucocytes  of  the  circulating  blood  in  9  cases,  8  of  which  showed 
the  tubercular  type  of  lesion. 


BIBLIOGRAPHY.  305 

Streker,  also,  examined  the  blood  of  5  "  very  anemic "  cases  of 
leprosy  and  found  bacilli  both  free  in  the  plasma  and  inclosed  in  leuco- 
cytes. The  blood  was  drawn  with  antiseptic  precautions  from  a  deep 
incision  through  normal  skin.  These  observations  are  quite  in  accord 
with  the  reports  of  Joseph  regarding  the  large  deposits  of  Bacillus 
leprce  in  the  spleen. 

Spronck  claims  that  the  serum  of  leprous  subjects,  in  dilutions  be- 
tween 1-60  and  1-1,000,  agglutinates  fresh  living  cultures  of  the  ba- 
cillus of  Hansen,  and  he  recommends  the  use  of  this  test  in  diagnosis. 

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Anc.  Monatshefte  f.  Prak.  Dermat.,  Bd.  12,  p.  266.  Virchow-Hirsch.  Jahresber., 
1892,  II.,  p.  537. 

Andral,  Oavarret.     Annal.  de  Chem.  et  de  Physiol.,  1840. 

Baginsky.     Lehrb.  d.  Kinderkrank.,  Berlin,  1889,  p.  287. 

Barbacci.     Cent.  f.  med.  Wissen.,  1887,  No.  35. 

Becquerel,  Bodier.  Cited  by  Wilbouchewitsch,  Arcliiv  de  Physiol,  norm,  et  path. 
1874,  p.  509.     Also,  Memoir  Acad,  des  Sci.,  1844. 

Bieganski.     Archiv  f.  Dermat.  u.  Syph.,  1892,  p.  43. 

Bierfreund.     Langenbeck's  Archiv,  Bd.  41,  p.  1. 

Brown.  Occidental  Med.  Times,  1897,  p.  537.  Also,  Trans.  California  Med.  Soc, 
1897,  p.  168. 

Cabot.     Boston  Med.  Surg.  Jour.,  1899,  Vol.  140,  p.  323. 

Canon.     Deut.  Zeit.  f.  Chirurg.,  Bd.  37,  p.  571. 

Bane.     Boston  Med.  Surg.  Jour.,  1896,  Vol.  134,  p.  559. 

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Bevoto.     Zeit.  f.  Heilk.,  Bd.  XL,  p.  176. 

Dieballa.     Deut.  Archiv  klin.  Med.,  Bd.  59,  p.  308. 

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Evdng.     N.  Y.  Med.  Jour.,  1893,  Vol.  58,  p.  713. 

Fenoglio.     Oesterreich  med.  Jahrb.,  1882,  p.  635. 

Fischl.     Zeit.  f.  Heilk.,  Bd.  13,  p.  291. 

Freund.     Wien.  med.  Jahrb.,  Bd.  1,  p.  335. 

Oaillard.     Gaz.  des  Hop.,  1885,  No.  74. 

Gartner,  Homer.     Wien.  klin.  Woch.,  1892,  No.  2. 

Gnezda.     Inaug.  Diss.  Berlin,  1886. 

Gross;'.     L'Union  Med.,  1859. 

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'Berl.  klin.  Woch.,  1900.^ 

Guttmann.     Cited  by  Kossel. 

Hammarschlag.     Zeit.  f.  klin.  Med.,  Bd.  21,  p.  475. 

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Heidenhain.     Pfliiger's  Archiv,  Bd.  49,  p.  209. 

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Hirschlaff.     Deut.  med.  Woch.,  1897,  p.  766. 

Jakowsky.     Cited  by  Sittmann. 

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Jones.     N.  Y.  Med.  Jour.,  1900,  Vol.  71,  p.  513. 

Joseph.     Archiv  f.  Dermat.  u.  Syph.,  Bd.  43,  p.  359. 

Justus.     Virchow's  Archiv,  Bd.  140,  p.  91.     Ibid.,  Bd.  140,  p.  533. 

Keyes.     Amer.  Jour.  Med.  Sci.,  1876,  Vol.  71,  p.  17. 

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Kossel.     Berl.  klin.  Woch.,  1891,  p.  302. 

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Kronig.     Deut.  med.  Woch.,  1894,  V.  B,  p.  42. 

Kuhnau.     Zeit.  f.  Hygiene,  Bd.  25,  p.  492. 

20 


306  SYPHILIS,  TUBERCULOSIS,  LEPROSY. 

Laache.     Die  Anemie,  1883,  p.  63. 

Laker.     Wien.  med.  Woch.,  1886,  No.  18. 

Lezius.     Blutver.  bei  Syphilitischen,  Diss.  Dorpat,  1889. 

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Limbeck,     i  Grundriss,  etc.,  p.  336.     « Cited  by  Kieder,  Leucocytose. 

Lindstrom.     Presse  Med.,  1898,  T.  13,  p.  267. 

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Malassez.     lArchiv  de  physiol.  norm,  et  path.,  1886.     "Prog.   Med.,  1874,  p.  562. 

Meisels.     Wien.  med.  Woch.,  1884,  p.  1187. 

Michaelis,  Meyer.     Charite-Annalen,  Bd.  22,  p.  150. 

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Petruschky.     Zeit.  f.  Hygiene,  Bd.  17,  p.  59. 

Pick.     Cited  by  Eieder. 

Reinert.     Zahlung  d.  Blutkorp,  p.  189. 

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Schlesinger.     Archiv  f.  exper.  Path.,  Bd.  13. 

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Stoukovenkoff.     Annal.  de  Dermat.,  1892,  p.  924. 

Strauer.     Zeit.  f.  klin.  Med.,  Bd.  24,  p.  295. 

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White.     Jour,  of  Exper.  Med.,  Vol.  IV.,  p.  425. 

Winiarski.     St.  Petersburg  med.  Woch.,  1892,  p.  365. 

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Ziemke.     Deut.  med.  Woch.,  1897,  Apr.  8,  cited  by  Cabot. 


PAET  IV. 
CONSTITUTIONAL  DISEASES. 

CHAPTER  XVII. 

HEMOERHAGIC    DISEASES    AND   THE   HEMOREHAGIC 

DIATHESIS. 

Hemorrhages  of  greater  or  less  extent  occur  iu  many  general  dis- 
eases, in  which  the  loss  of  blood  is  not  referable  to  any  specific  predispo- 
sition on  the  part  of  the  individual  but  to  peculiar  conditions  arising  in  the 
course  of  the  disease.     Such  hemorrhages  are  regarded  as  symptomatic. 

The  chief  causes  of  symptomatic  hemorrhages  are  : 

1.  Infections,  as  in  many  severe  infectious  diseases  such  as  septi- 
cemia, scarlatina,  smallpox,  measles,  etc. 

2.  Mechanical,  as  in  partly  asphyxiated  infants,  or  other  conditions 
of  marked  venous  stasis. 

3.  Toxic  and  autotoxic,  as  in  poisoning  by  the  so-called  blood- 
poisons,  or  in  jaundice,  anemia,  etc. 

4.  Nervous,  as  in  rare  forms  of  hysteria. 

In  the  hemorrhagic  diathesis  probably  all  the  above  factors  are  at 
times  unusually  active  but  there  is  believed  to  be  in  addition  a  specific, 
preexisting,  often  hereditary  change  iu  the  blood  which  largely  deter- 
mines the  various  manifestations  of  this  diathesis.  Modern  bacterio- 
logical and  chemical  research  has  now  considerably  narrowed  the  scope 
of  the  hemorrhagic  diathesis,  and  at  present  it  is  impossible  to  claim 
that  any  peculiar  predisposition  to  hemorrhage  exists  except  in  cases  of 
hemophilia.  Yet  it  remains  convenient  to  describe  the  various  idio- 
pathic purpuras,  scurvy,  and  hemophilia,  as  closely  related  conditions. 

PURPURA   HEMORRHAGICA.     WERLHOFF'S    DISEASE. 

The  etiology  of  this  disease  still  remains  obscure,  although  the  evi- 
dence points  more  and  more  toward  some  form  of  infection  as  the  es- 
sential element  in  the  majority  of  cases.  The  prominence  of  hemor- 
rhage in  the  symptoms  of  many  infectious  diseases  has  prepared  the 
way  for  an  acceptance  of  this  view.  In  adults,  the  extent  of  the 
hemorrhage  attending  well  identified  forms  of  infection  is  rarely  so 
great  as  in  pronounced  cases  of  purpura  hemorrhagica,  in  which  often 
no  bacterial  origin  has  been  demonstrable.     In  infants,  however,  in- 


308  HEMORRHAGIC  DISEASES  AND  HEMORRHAGIC  DIATHESIS 

fections  by  the  ordinary  pyogenic  bacteria  have  become  recognized  as 
a  frequent  source  of  fatal  hemorrhages  constituting  for  that  age  the 
typical  picture  of  WerlhoiF's  disease. 

There  are  now  mauj'^  cases  of  purpura  hemorrhagica  on  record  in  which 
bacteriological  examination  of  the  blood  or  viscera  showed  the  presence  of 
bacteria  which  were  regarded  as  the  cause  of  the  disease.  In  some  cases 
bacilli  were  isolated,  which  were  not  fully  identified.  Letzerich's  Bacillus 
purpurse  in  many  respects  resembled  Bacillus  anthracis,  and  produced  in  ani- 
mals, and  possibly  in  the  investigator's  own  person,  a  hemorrhagic  disease 
resembling  Werlhoff 's.  Streptococcus  pyogenes  has  been  isolated  in  typical 
cases  by  Hanot  and  Luzet,  Widal  and  Therese,  Guarnieri,  and  others.  In  the 
first  of  these  the  disease  was  transmitted  from  mother  to  fetus,  the  latter 
dying  and  yielding  a  pure  culture  from  the  blood.  In  infants,  rapidly  fatal 
hemorrhagic  infections  of  this  nature  are  not  rare. 

Staphylococcus  pyogenes  aureus  has  been  isolated  by  Lebreton,  Litten, 
Fischl  and  Adler,  Lewis,  Silvestrini,  and  others.  Fischl  and  Adler  claim  to 
have  produced  a  fatal  anemia  in  animals  by  inoculation  with  their  coccus. 
Kolb  obtained  sterile  cultures  of  the  blood  in  5  cases,  but  from  the  viscera  of 
three  of  these,  3-4  hours  after  death,  he  isolated  a  diplobacillus  which  caused 
hemorrhagic  septicemia  in  various  animals.  Auche  obtained  both  the  staph- 
ylococcus and  streptococcus  in  a  fatal  case,  and  Levi  obtained  in  another 
both  Streptococcus  pyogenes  and  the  pneumococcus  of  Frankel. 

The  Pneumococcus  lanceolatus  was  isolated  post-mortem  by  Claisse  and 
by  Claude.  Bacillus  pyocyaneus  was  obtained  post-mortem  from  a  case  of 
melena  neonatorum  by  Neumann,  and  Bacillus  coli  communis  by  Dansac, 
Legendre,  and  others.  Hamilton  and  Yates  report  a  rapidly  fatal  case 
showing,  ten  hours  post-mortem.  Bacillus  aerogenes  capsulatus.  McLeod  ob- 
served a  case  closely  following  Malta  fever,  and  conditions  described  as  pur- 
pura hemorrhagica  have  been  reported  as  following  pertussis,  tuberculosis, 
congenital  syphilis,  etc.  Negative  results  are  reported  in  a  fatal  case  by 
Denys  ;  in  a  purpuric  complication  of  angina,  by  Legendre  ;  and  in  chronic 
cases  by  Marfan,  and  by  Millard. 

In  the  majority  of  the  above  cases  the  bacterium  was  obtained  post- 
mortem and  from  the  viscera,  or  during  life,  from  the  lesions  in  the 
skin,  and  was  rarely  demonstrated  in  the  circulating  blood.  Never- 
theless there  can  be  but  little  doubt  that  a  numerous  group  of  cases  of 
purpura  hemorrhagica  exists  Avhich  is  referable  to  a  variety  of  bacteria, 
as  represented  in  the  above  reports. 

It  seems  necessary  therefore  to  provisionally  separate  the  cases  of  pur- 
pura hemorrhagica  of  probable  infectious  origin  from  those  which  in  no 
respect  resemble  an  infectious  disease,  and  are  therefore  probably  acute 
manifestations  of  hemophilia. 

Changes  in  the  Blood. — In  most  of  the  febrile  infectious  cases  oi pur- 
pura hemorrhagica  the  anemia  is  not  excessive  and  appears  to  be  sec- 
ondary to  the  infection  and  the  loss  of  blood.  In  mild  cases  the  red 
cells  are  slightly  diminished  in  number  but  exhibit  no  other  alterations. 
Carriere  and  Gilbert  report  cases  with  3.35  million  and  3.9  million 
red  cells,  many  of  which  were  microcytes.  In  more  severe  cases  the 
red  cells  may  be  greatly  diminished,  in  proportion  to  the  extent  of 
hemorrhage,  but  a  microcytic  type  of  red  cell  is  usually  prominent. 
The  Hb-index  is  subnormal.  Nucleated  red  cells  occur  when  hemor- 
rhages are  large  or  frequent. 


NON-INFECTIOUS  IDIOPATHIC  PUEPURA  HEMORRHAGICA.   309 

In  a  fatal  case  in  an  infant,  yielding  a  pure  culture  of  Streptococcus 
pyogenes  at  post-mortem,  the  writer  found  the  blood  to  show  all  the 
characteristics  of  primary  pernicious  anemia.  In  4  other  cases  of  fatal 
hemorrhage  in  newborn  infants  at  Sloane  Maternity  Hospital,  the 
subjects  had  bled  to  death  in  the  course  of  3-5  days,  but  the  blood 
showed  only  the  characteristics  of  secondary  anemia  with  leucocyto^is. 
Leucocytosis  has  been  noted  by  the  majority  of  observers.  In  one 
case  Carriere  and  Gilbert  found  126,000  leucocytes,  90  percent  poly- 
nuclear,  and  5.8  percent  eosinophile.  In  the  writer's  cases  in  infants 
the  leucocytosis  reached  as  high  as  56,000,  but  the  eosins  were  scanty. 
A  very  marked  degree  of  polychromatophilia  was  observed  in  two 
cases  by  Spietschka. 

Hayem'  and  Bensaude  have  described  a  peculiarity  in  the  blood  of 
purpura  hemorrhagica  which  they  claim  to  be  pathognomonic.  On 
allowing  the  blood  to  clot  in  a  vessel  it  was  found  that  after  24  hours 
the  retraction  of  the  coagulum  is  very  feeble  and  fails  to  express  the 
serum,  as  happens  in  normal  blood.  Associated  with  this  feeble  coagu- 
lation there  is  a  marked  reduction  of  blood  plates  (200,000  to  50,000). 
These  two  features  of  the  blood  were  noted  in  16  cases  of  purpura 
hemorrhagica,  but  in  152  examples  of  other  diseases,  some  with  pur- 
pura, the  feeble  clotting  and  loss  of  blood  plates  were  never  found  to 
be  combined. 

Non-infectious  Idiopathic  Purpura  Hemorrhagica. — In  addition 
to  the  cases  of  purpura  which  arise  in  the  course  of  infectious  diseases 
or  after  various  infectious  processes,  in  which  hemorrhage  constitutes 
the  chief  symptom  of  a  cryptogenic  infection,  there  are  other  cases  of 
rapidly  fatal  anemia  attended  with  severe  and  repeated  losses  of  blood 
for  which  a  diiferent  etiology  is  indicated. 

Some  of  these  cases  are  difficult  to  distinguish  from  pernicious 
anemia,  but  differ  from  that  disease  in  the  absence  of  megaloblastic 
changes  in  the  blood  or  marrow,  the  great  predominance  of  microcytes 
in  the  blood,  and  the  prominence  of  hemorrhage  among  the  symptoms. 
They  differ  from  the  infectious  purpura  in  the  more  persistent  hemor- 
rhage, the  absence  of  leucocytosis,  and  the  absence  of  general  symp- 
toms of  an  infectious  disease. 

Such  cases  have  been  reported  by  Ehrlich,^  Engel,  and  others,  as 
pernicious  anemia  without  characteristic  changes  in  the  blood  or  mar- 
row. The  writer  can  find  no  evidence  on  which  to  claim  that  per- 
nicious anemia  can  exist  without  such  changes  in  the  marrow,  and 
believes  that  these  cases  belong  to  the  diseases  referable  to  the  hemor- 
rhagic diathesis.  This  view  is  supported  not  only  by  the  great  dis- 
similarity in  the  blood  changes  of  the  two  conditions  but  by  the  ab- 
sence of  any  marked  deposits  of  iron  in  the  viscera.     (Zalesky.) 

Of  the  various  etiological  factors  to  which  fatal  purpura  has  been 
attributed  the  non-infectious  variety  may  be  referred  to  any  or  all  ex- 
cept the  presence  of  bacteria.  The  underlying  condition  is  probably 
identical  with  that  of  hemophilia  of  more  typical  course. 

Changes  in  tlie  Blood. — The  red  cells  are  rapidly  diminished  in  num- 


310  HEMORRHAGIC  DISEASES  AND  HEMORRHAGIC  DIATHESIS. 

ber,  reaching  before  death  an  extremely  low  figure.  In  a  case  of  the 
writer's  persistent  epistaxis  reduced  them  in  three  weeks  to  456,000. 
In  a  case  reported  by  Billings  they  numbered  483,000.  In  Engel's 
case  there  were  over  two  millions.  Contrary  to  the  rule  in  secondary 
anemia  following  hemorrhage,  nucleated  red  cells  are  extremely  scarce 
or  absent.  The  majority  of  the  red  cells  are  undersized  and  many  are 
of  oval  shape.  The  leucocytes  are  normal  or  reduced  in  number  and 
of  those  remaining  a  large  proportion  (90  percent,  Engel ;  80  percent, 
Ehrlich  ;  75  percent,  Billings)  are  lymphocytes.  Eosinophile  cells 
are  scarce  or  absent. 

HEMOPHILIA. 

Hemophilia  is  an  extremely  hereditary  constitutional  anomaly  which 
predisposes  the  subject  to  persistent  and  fatal  hemorrhages  of  traumatic 
or  spontaneous  origin.  The  peculiar  law  of  heredity  which  transmits 
the  condition  to  males,  only  through  the  female  parents  who  are  them- 
selves usually  exempt,  as  fully  set  forth  by  Grandidier  and  Stahel, 
not  only  marks  this  malady  as  the  clearest  possible  illustration  of  the 
hereditary  transmission  of  disease  but  completely  baffles  the  attempts 
to  prove  its  dependence  on  any  infectious  agent. 

The  essential  lesion  has  been  held  by  many  to  lie  in  an  unnatural 
thinness  and  narrowness  of  the  arteries  (Virchow).  In  somewhat  altered 
form  this  theory  is  maintained  by  Immerman  and  Oertel,  who  hold 
that  there  is  a  disproportion  betioeen  the  bulk  of  blood  and  the  capacity  of 
the  blood  systeni,  referable  in  part  to  hypoplasia  of  vessels  (Immerman) 
or  to  hydremic  plethora.  Proceeding  on  this  theory  Cohen  claims  to 
have  considerably  lessened  the  tendency  to  hemorrhage  in  a  pro- 
nounced bleeder  by  a  prolonged  course  of  diuresis  and  diaphoresis. 
In  partial  support  of  this  mechanical  theory  are  cited  a  few  cases  in 
which  the  heart  was  hypertrophied,  and  the  vessels  of  small  size,  and 
showing  fatty,  hyaline,  or  granular  degeneration. 

A  locfd  origin  is  perhaps  indicated  by  the  case  cited  by  Stengel,  in 
which  the  hemorrhages  were  observed  to  occur  from  cuts  above  the 
neck  but  never  from  those  below. 

Hecklinghausen  holds  that  a  disorder  of  the  nervous  system  is  the 
essential  cause  of  the  hemorrhages,  and  Henoch  believes  that  the  local 
condition  is  one  of  paralytic  dilatation  of  vessels,  followed  by  diapede- 
sis.  The  condition  has  been  seen  in  some  very  remarkable  forms  in 
neurotic  and  hysterical  subjects.      (Stengel.) 

Little  success  has  followed  numerous  attempts  to  demonstrate  essen- 
tial changes  in  the  blood.  Albertoni  claims  to  have  found  dimin- 
ished resistance  in  the  red  cells.  In  morphology  there  is  uniform 
agreement  that  the  blood  presents  nothing  peculiar.  Decreased  coagu- 
lability was  held  to  be  constant,  by  older  writers  (Grandidier,  Lossen), 
and  has  later  been  observed  by  Schmidt  and  ManteufiFel,  who  found 
that  the  blood  in  hemophilia  requires  longer  than  usual  to  clot,  Avhile 
its  coagulation  may  be  greatly  hastened  by  adding  a  zymoplastic  sub- 
stance  (fibrin  ferment).     The  fibrin  itself  is  apparently  not  greatly 


SCURVY.  311 

diminished,  5  percent  having  been  found  by  Hey  land,  2.6  percent  by 
Gavoy  and  Ritter,  and  4.3  percent  by  Otto  (cited  by  Litten). 
''  Koch's  theory  of  the  infectious  origin  of  hemophilia  seems  hardly 
worth  discussing."     (Litten.) 

Studies  in  pathological  anatomy  have  also  failed  to  show  any  con- 
stant lesion  of  essential  importance.  In  most  of  the  viscera  there  are 
the  lesions  which  follow  acute  or  chronic  anemia.  Buhl  described  an 
unusually  rich  network  of  capillaries  in  the  skin  of  one  case,  but  the 
tissue  was  the  seat  of  a  chronic  inflammatory  process.  Birch-Hirsch- 
feld  found  normal  vessels,  slightly  fatty  heart  muscle,  and  slight 
hyperplasia  of  the  splenic  stroma.  Litten  noted  areas  of  granular  de- 
generation in  capillary  endothelium,  and  irregularity  in  outline  or 
widening  of  intercellular  spaces  between  these  cells,  but  suspected 
these  changes  to  be  artificial.  In  a  series  of  cases  hypoplasia  of  the 
heart  furnished  the  basis  of  Virchow's  theory. 

The  blood  changes  are  determined  by  the  extent  of  the  hemorrhages, 
but  leucocytosis  has  been  absent  in  the  few  cases  reported.  In  general 
the  blood  resembles  that  of  non-infectious  purpura  hemorrhagica. 


SCURVY. 

Etiology. — The  most  important  fact  in  the  etiology  of  scurvy  is  its 
intimate  relation  to  improper  diet.  Aside  from  the  almost  exclusive 
occurrence  of  the  disease  in  subjects  whose  food  has  been  restricted  in 
variety,  it  has  been  repeatedly  demonstrated  that  the  malady  may  be 
promptly  cured  by  supplying  some  element  previously  deficient  in  the 
diet.  Even  a  change  in  water  supply  has  eradicated  epidemics  in 
garrisons.  Scorbutic  infants  rapidly  recover  from  grave  stages  of  the 
disease  after  such  apparently  trivial  assistance  as  a  change  in  the  milk. 
Yet  it  has  never  been  fully  determined  just  what  chemical  substance  is 
concerned  in  the  causation  and  cure  of  the  disease.  It  has  even  been 
claimed  that  diet  has  no  relation  to  the  malady,  but  all  such  reports 
have  thus  far,  on  investigation,  failed  to  be  supported,  although  they 
have  demonstrated  that  the  dietetic  error  may  be  very  trivial.  Thus 
Seelaud,  regarding  a  somewhat  limited  army  ration  as  full  mixed  diet, 
came  to  regard  the  cases  of  scurvy  under  his  care  as  of  miasmatic 
origin.  Accumulating  evidence  has  shown  that  the  most  frequent 
source  of  the  disease  is  a  too  exclusive  diet  of  meat,  especially  if  salted, 
and  the  absence  of  fresh  vegetables,  especially  of  potatoes,  which  are 
very  rich  in  potassium. 

Guided  by  these  observations  various  theories  of  origin  of  scurvy  have  been 
elaborated,  only  to  be  disproved  by  later  study.  Among  these  is  the  belief 
that  the  symptoms  were  caused  by  excess  of  NaCl  in  the  blood,  a  condition 
long  since  shown  to  characterize  most  forms  of  anemia.  That  the  essential 
element  in  the  disease  consists  in  a  deficiency  of  potassium  in  the  blood  was 
held  by  Garrod,  Liebig,  and  Hirscli,  but  a  loss  of  potassium  from  the  blood, 
with  excess  in  the  urine,  while  not  constant  in  scurvy,  is  observed  in  other 
conditions.     Similarly  the  opinion  of  Ralfe  and  Cantani,  that  a  deficiency  of 


312  HEMORRHAGIC  DISEASES  AND  HEMORRHAGIC  DIATHESIS 

salts  of  vegetable  organic  acids  and  corresponding  diminution  in  the  alka- 
linity of  the  blood  is  the  important  factor,  has  failed  to  receive  support. 

Nevertheless  to  those  who  have  observed  the  immediate  effects  of 
correction  of  diet  in  severe  cases,  especially  in  children,  this  field  of 
investigation  appears  most  likely  to  offer  the  true  explanation  of  the 
disease,  for  which  the  sole  hope  is  an  advance  in  our  knowledge  of  the 
chemistry  of  digestion  and  absorption,  and  of  the  blood. 

On  the  other  hand  there  are  on  record  some  very  suggestive  bacteri- 
ological studies  of  scurvy,  pointing  toward  an  infectious  nature  of  the 
disease.  The  injection  into  animals  of  blood  from  scorbutic  patients 
caused  purpuric  lesions  and  internal  hemorrhages  in  the  experiments 
of  Murri,^  Petrone,  and  others.  Babes  failed  to  find  bacteria  in  the 
blood  of  a  series  of  cases  and  failed  to  produce  significant  lesions  by 
injecting  blood  into  animals,  but  from  excised  portions  of  the  spongy 
gums  he  isolated  a  bacillus,  regarded  as  identical  with  one  previously 
described  by  Muller  as  common  in  the  buccal  cavity,  and  by  injections 
of  the  comminuted  tissue  he  produced,  in  two  out  of  a  series  of  rab- 
bits, a  form  of  hemorrhagic  septicemia.  From  the  visceral  lesions  he 
recovered  this  same  bacillus  along  with  the  ordinary  bacillus  of  hemor- 
rhagic septicemia  in  rabbits.  It  does  not  appear  that  much  significance 
can  be  attached  to  these  results,  although  they  are  commonly  quoted 
as  strongly  supporting  the  infectious  theory  of  the  origin  of  scurvy. 
Rosenell  also  recovered  a  somewhat  similar  bacillus  from  the  viscera 
of  a  fatal  case  of  scurvy,  but  inoculations  into  rabbits  were  negative. 
Entirely  negative  results  were  obtained  by  AVieruszky  in  a  large  num- 
ber of  cases.  Most  of  his  cultures  of  the  blood  were  sterile,  but  in  14 
cases  he  found  various  germs  to  which  he  could  not  assign  any  relation 
to  the  disease. 

In  recent  years  the  bacteriological  study  of  scurvy  has  not  proved 
an  inviting  or  accessible  field  to  competent  bacteriologists. 

A  recent  impox'tant  study  directed  toward  the  chemistry  of  the  blood  and 
of  digestion  is  that  of  Albertoni,  who  has  shown  that  there  is  a  marked  loss 
or  complete  absence  of  free  HCl  in  the  gastric  juice  in  scorbutic  patients, 
that  gastric  digestion  is  deficient,  that  intestinal  putrefaction  is  excessive, 
and  that  there  are  abundant  evidences  in  the  urine  of  absorption  of  toxic 
products,  while  the  absorption  of  fats  and  carbohydrates  is  deficient.  In 
the  blood,  Albertoni  found  a  much  greater  reduction  in  iron  (.3-.39  percent) 
than  is  seen  in  other  anemias  with  equal  numbers  of  red  cells.  The  sodium 
and  potassium  varied  between  normal  limits.  The  greenish  yellow  color  of 
the  serum  and  the  excess  of  pigments  in  the  urine  were  evidences  of  active 
destruction  of  blood  cells. 

Changes  in  the  Blood. — The  morphological  changes  in  the  blood 
in  scurvy  resemble  those  of  secondary  anemia  from  hemorrhage. 

The  red  cells  in  cases  of  average  severity  number  between  3  and  4 
millions,  but  with  severe  hemorrhages  the  anemia  may  become  very 
grave,  as  in  Bouchut's  case  in  which,  after  three  weeks  of  persistent 
epistaxis,  the  red  cells  were  reduced  to  557,000.  The  reports  of  Us- 
kow,  Hayem,^  Wieruschky,  and  Albertoni,  show  that  the  red  cells  vary 


HEMOCYTOL  YSIS.  313 

in  number  and  size  according  to  the  length  and  severity  of  the  disease. 
Litten  saw  many  megalocytes  and  shrunken  microcytes,  evidently  in 
severe  cases.  Albertoni  found  evidences  of  solution  of  red  cells  in  the 
plasma,  and  an  excessive  number  of  pale  cells  or  fragments  of  cells 
have  been  described  by  several  observers.  The  Hb-index  is  low, 
White  finding  20  percent  Hb  with  40  percent  of  red  cells,  while  Bec- 
querel  and  Albertoni  found  the  iron  content  much  lower  than  in  other 
anemias.  Opitz  and  Duchek,  however,  reported  a  normal  or  increased 
proportion  of  iron. 

The  proportions  of  sodium  and  potassium  salts  vary  as  in  other 
anemias,  and  the  claims  of  Ralfe  and  Cantani  that  the  alkalinity  of 
the  blood  is  deficient  have  not  been  supported. 

On  account  of  the  frequency  of  inflammatory  complications  and 
hemorrhages  the  leucocytes  are  usually  increased,  Uskow  finding  as 
high  as  47,000.  Litten,  however,  observed  no  leucocytosis,  and  the 
writer,  in  two  well-marked  but  uncomplicated  cases,  found  no  increase. 

In  Barlow's  disease,  which  is  a  form  of  scurvy  with  extensive  sub- 
periosteal hemorrhages,  the  condition  of  the  blood  varies  greatly,  ac- 
cording to  the  general  condition  of  the  patient  and  the  number  and  ex- 
tent of  the  hemorrhages.  All  grades  of  post-hemorrhagic  anemia  have 
been  observed,  up  to  Reinert's  fatal  case  in  which  the  Hb  fell  to  17 
percent  and  the  red  cells  to  976,000.  The  disease  is  often  associated 
with  rachitis. 

HEMOOYTOLYSIS. 

When  the  isotonic  tension  of  the  plasma  falls  below  that  of  the  red 
cells,  the  Hb  may  become  dissolved  in  the  circulating  blood,  and  the 
shadow-like  remnants  of  the  stroma  of  the  cells  are  distributed  in  the 
plasma.  In  other  conditions,  even  without  lowered  isotonic  tension  of 
the  plasma,  the  red  cells  may  be  split  up  into  fragments.  The  purest 
examples  of  the  former  variety  of  destruction  of  red  cells  are  perhaps 
seen  after  extensive  infusions  of  salt  solution,  while  the  latter  variety 
is  observed  especially  from  the  effects  of  certain  blood  poisons,  e.  g., 
potassium  chlorate.  Usually  the  two  processes  are  combined,  as  in 
the  anemias  and  infectious  diseases,  while  in  some  conditions  the  exact 
manner  of  the  solution  of  Hb  remains  unexplained. 

The  chemical  processes  in  the  cell  leading  to  the  solution  of  Hb  are 
somewhat  obscure,  since  this  constituent  is  probably  held  in  chemical 
combination  with  the  stroma  and  not  merely  held  in  situ  by  a  hypo- 
thetical cell  membrane.  Thus  the  most  extreme  form  of  hemoglobi- 
nemia  (paroxysmal)  may  occur  in  blood  of  comparatively  high  isotonic 
tension,  while  the  high  grades  of  globulicidal  activity  of  the  plasma  in 
infectious  diseases  are  not  always  associated  with  hydremia. 

The  morphological  changes  occurring  in  dissolving  red  cells  are  also 
not  fully  identified,  although  it  appears  more  and  more  probable  that 
many  forms  of  degeneration  previously  described  in  red  cells  are  the 
precursors  of  the  complete  solution  of  Hb.  The  polychromatic  de- 
generation of  Maragliano,  that  of  Gabritschewsky,  and  the  granular 


314  HE3I0BBHAGIC  DISEASES  AND  HEMORRHAGIC  DIATHESIS 

degeneration  of  Grawitz,  are  probably  morphological  signs  indicating 
approaching  or  progressive  solution  of  the  cell.  From  extensive  study 
of  the  anemia  following  pyrodin  poisoning  Tallquist  concludes  that  the 
presence  of  microeytes  is  a  sign  of  hematolysis,  while  megalocytes  indieate 
regeneration  of  the  blood.  The  dissolved  Hb  imparts  to  the  plasma,  in 
the  eosin-stained  specimen,  an  abnormal  reddish  tinge,  and  discolors 
the  serum.  When  present  in  moderate  amount  it  may  be  gradually 
transformed  by  the  liver  into  bile-pigment,  which  is  occasionally  reab- 
sorbed from  the  biliary  passages,  causing  hematogenous  jaundice.  The 
presence  of  an  excessive  amount  of  Hb  in  the  plasma  is  apparently  the 
chief  reason  why  it  is  sometimes  excreted  by  the  kidneys  and  appears 
in  the  urine  as  hemoglobin  or  methemoglobin.     During  its  passage 

through    the    liver,  kidney. 
Fig.  24.  and    other    tissues,    a    con- 

siderable portion  of  the  iron 
is  retained  in  the  demonstra- 
ble granular  or  diffuse  form 
of  hemosiderin. 

Under     some    conditions 
not    fully    understood,    but 
believed  by  Thoma  to  consist 
essentially    in    the    relative 
absence  of  oxygen,  disinte- 
grating red  cells  are  trans- 
formed largely  into  brown- 
ish granules  or   crystals  of 
hematoidin.      This     change 
usually  takes  place  without 
the  intervention  of  cellular 
activity.     (Thoma.)     It  fre- 
quently occurs  post-mortem. 
Broken  fragments  of  red 
cells  and  the  stroma  of  dis- 
integrated corpuscles  float  in  the  plasma  for  a  time  and  may  be  observed 
in  the  stained  specimen,  but  are  gradually  englobed  by  phagocytic  cells 
and  lodged  in  various  organs,  principally  in  the  spleen. 

The  anemia  of  the  infectious  diseases,  especially  in  grave  septic 
conditions,  is  established  rapidly  and  to  a  large  extent  through  the  di- 
rect solution  of  red  cells  by  the  globulicidal  plasma.  The  condition 
is  often  attended  during  life  by  hemoglobinuria,  and  after  death  ex- 
tensive deposits  of  blood  pigment  are  found  in  all  viscera,  especially 
in  the  spleen  and  liver. 

In  malaria  various  forms  of  destruction  of  red  cells  occur,  which 
will  be  considered  later. 


Acute  degeneration  of  red  cells.  Nitro-benzol  poison- 
ing. (K.  Ehrlich,  LiNDENTH.\L. )  Subdivision  of  ccUs 
and  appearance  of  basophilic  granules  in  them. 


Special  Conditions  in  Which  Blood  Cells  Are  Rapidly  Destroyed. 

General   Burns. — The  remarkable  effect  of  high  temperatures  in 
splitting  up  red  cells  may  be  readily  observed  by  heating  a  fresh  spec- 


SALT  SOLUTION,  SERUM,  AND  DEFIBRINATED  BLOOD.       315 

imen  over  a  flame.  Schmidt  found  that  this  effect  occurs  with  tem- 
peratures above  50°  C.  The  writer  failed  to  find  any  traces  of  disin- 
tegrated red  cells  in  a  series  of  rabbits  exposed  for  other  purposes  to  a 
temperature  of  45-46°  C.  In  animals  that  had  been  scalded  Wertheim 
found  many  subdivided  red  cells.  In  fatal  cases  of  burns  in  the 
human  subject  similar  eifects  may  be  observed,  but  not  in  a  degree 
sufficient  to  cause  death,  which  must  result  from  other  factors.  That 
hemoglobin  may  be  dissolved  in  the  plasma  and  appear  in  the  urine 
after  burns  is  stated  by  Hoppe-Seyler. 

Snake  poison  contains  a  toxic  globulin  or  albumen  which  dissolves 
red  cells  and  produces  hemoglobinemia  and  hemoglobinuria. 

Fumes  of  arseniuretted  hydrogen  are  very  active,  when  inhaled, 
in  dissolving  red  cells,  producing  hemoglobinemia,  hemoglobinuria, 
with  Hb-infarcts  in  the  kidneys,  and  acute  degeneration  of  the  viscera. 

Poisoning"  by  toadstools,  by  the  alkaloids  of  Quillaia  saponaria 
(saponin,  sapotoxin),  of  Solanum,  and  other  motor-depressants,  dis- 
solves red  cells  in  the  blood,  and  leads  to  hemoglobinuria.     (Robert.) 

In  a  fatal  case  of  poisoning  by  Guiacol,  Wyss  observed  rapid  de- 
struction of  red  cells,  finding  many  degenerated,  fragmented,  shrunken 
red  cells  and  megalocytes,  on  the  second  to  third  days.  The  white  cells 
were  considerably  increased  and  the  majority  of  these  were  lymphocytes. 

Nitrites. — Poisoning  by  nitroglycerin  and  by  amyl  nitrite  is  said  to 
occur  in  the  manufacture  of  these  chemicals,  and  to  be  followed  by 
methemoglobinemia. 

Nitrobenzol  poisoning  was  studied  in  a  fatal  case  by  K.  Ehrlich 
and  Lindenthal. 

Ten  hours  after  the  initial  symptoms  the  blood  was  chocokite  colored,  the 
serum  brownish,  and  spectral  analysis  sliowed  the  presence  of  methemo- 
globiu,  which  disappeared  by  the  eighth  day.  The  red  cells  were  rapidly 
reduced,  2,275,000  on  the  fifth  day,  and  falling  to  900,000  before  death  on 
the  nineteenth  day.  Poikilocytosis  appeared  on  the  third  day  and  soon 
reached  a  remarkable  degree.  Polychromatic  and  fragmented  cells  were 
abundant.  Nucleated  red  cells  were  first  seen  on  the  third  day,  and  there- 
after in  very  large  numbers  and  of  all  sizes.  On  the  ninth  day  the  leuco- 
cytes, previously  low,  rose  suddenly  to  61,000,  and  the  nucleated  red  cells 
were  reported  at  24,700.  .Tudgiug  from  the  authors'  plates  it  was  perhaps 
difficult  to  distinguish  between  karyorhexis  in  some  nucleated  cells  and  ex- 
treme forms  of  the  granular  degeneration  of  Grawitz.  The  Hb  fell  steadily 
to  40  percent,  which,  with  900,000  cells,  was  a  remarkably  high  Hb-index. 
There  were  many  myelocytes  among  the  white  cells,  so  that  at  one  time  the 
blood  jiresented  the  appearance  of  leukemia.  The  bone  marrow  was  not 
examined.  These  interesting  observations  recall  the  efforts  of  Bignami  and 
Dionisi  to  produce  experimental  pernicious  anemia  bj'  means  of  toluendia- 
min.  The  morphological  characters  of  the  blood  described  by  Ehrlich  and 
Liudenthal  probably  represent  an  extreme  degree  of  the  effects  upon  the 
blood  of  the  entire  group  of  anilin  poisons. 

Transfusion  of  Salt  Solution,  Serum,  and  Defibrinated  Blood. — 

Siegel  and  Schram  both  found  no  improvement  in  the  regeneration  of 
the  blood  from  the  transfusion  of  salt  solution  or  of  serum  in  animals 
after  bleeding,  and  while  it  has  since  been   shown  that  the  regenera- 


316  HEMORRHAGIC  DISEASES  AND  HEMORRHAGIC  DIATHESIS. 

tion  is  somewhat  more  rapid  and  complete  after  salt  infusion,  yet  this 
procedure  must  be  regarded  as  of  more  value  as  a  means  of  saving  life 
than  as  a  stimulant  to  blood  formation.  The  direct  effects  on  the 
blood  of  infusion  of  defibrinated  blood  seem  to  be  much  more  favorable. 
On  the  other  hand,  after  the  transfusion  of  blood,  the  above  observers, 
and  others,  have  found  a  rapid  increase  in  the  number  of  cells,  and 
Bizzozero  reported  the  same  effect  after  transfusion  of  defibrinated 
blood  in  animals.  Quincke  was  one  of  the  first  to  note  an  increase 
in  red  cells  in  pernicious  anemia  as  a  result  of  transfusion  of  blood, 
and  similar  observations  have  been  made  by  Ziemann  in  anemia  and 
scurvy.  It  would  seem,  from  the  observations  of  Bizzozero  and  of 
Bareggi,  that  the  red  cells  are  quite  resistant  to  the  process  of  defibrina- 
tion and  injection.  Of  the  immediate  effects  of  salt  infusion  upon  the 
blood  of  the  human  subject  there  are  a  few  reports  at  hand  which  in- 
dicate that  it  has  considerable  influence  in  lowering  the  number  of  red 
cells  and  increasing  the  leucocytes. 

Methemoglobinemia. — ^Various  poisons  not  only  dissolve  red  cells, 
but  at  once  transform  the  hemoglobin  into  methemoglobin.  The  blood 
in  such  cases  may  exhibit  a  distinct  chocolate  color. 

Potassium  chlorate  is  one  of  the  most  frequent  forms  of  poison- 
ing which  cause  destruction  of  red  cells  with  methemoglobinemia. 
According  to  v.  Mering  the  KCIO3  acts  directly  upon  the  cells  and 
is  itself  thereby  reduced,  while  INIarchand,  Falck,  and  others,  hold  that 
the  serum  is  first  altered.  Brandenburg  reports  a  fatal  case  in  which 
the  red  cells  fell  in  6  days  from  4.3  to  1.6  millions.  Many  of  them  were 
deformed.  The  blood  and  serum  were  chocolate  colored  and  gave, 
during  the  first  5  days  only,  the  spectrum  of  methemoglobin.  There 
was  marked  leucocytosis  (20,000). 

Sticker  reports  a  severe  case  of  poisoning  after  a  vaginal  douche  by 
solution  of  chromic  acid,  the  patient  passing  brownish  urine.  He  re- 
fers to  other  fatal  cases  with  similar  signs. 

Pyrogallol  and  pyrogallic  acid  have  caused  death  with  symptoms  of 
methemoglobinemia.     (Grawitz.) 

Antifebrine  has  been  found  to  produce  extreme  methemoglobinemia 
in  animals  (Lepine)  and  in  man  (Muller),  but  neither  of  these  ob- 
servers could  find  any  morphological  changes  in  the  blood  of  subjects 
dying  from  this  cause. 

Antipyrine  produces  toxic  symptoms  similar  to  those  of  antifebrine, 
but  reports  on  the  examination  of  the  blood  in  severe  cases  are  want- 
ing.    (See  Falk,  Muller.) 

Poisoning  by  CO. — A  bright  cherry  red  color  of  the  blood  is  a  char- 
acteristic sign  in  cases  of  "  gas  poisoning,"  and  is  referable  to  the 
presence  of  CO-Hb.  The  methods  of  diagnosis  of  this  condition  by 
spectral  analysis  have  already  been  considered.     (See  p.  25.) 

Poisoning  by  Hydrocyanic  Acid. — The  bright  red  color  of  the  blood 
in  this  condition  is  referable  to  the  presence  of  cyan-methemoglobin 
(Robert),  which  gives  a  characteristic  spectrum.  The  manner  of 
death  is  believed  by  Geppert  to  be  through  inhibition  of  the  metabolic 


POST-MALARIAL  HEMOOLOBINEMIA.  317 

processes  in  tissues,  so  that  CO  is  not  discharged  and  oxygen  not  ab- 
sorbed.    Morphological  changes  in  the  blood  have  not  been  reported. 

Paroxysmal  Hemoglobinuria. — This  remarkable  condition,  con- 
sisting essentially  in  the  rapid  solution  in  the  blood  stream  of  enormous 
numbers  of  red  cells,  followed  by  the  appearance  of  Hb  in  the  urine, 
was  recognized  by  Stewart  more  than  a  century  ago  (1794),  and  has 
been  widely  studied  in  its  various  phases  ever  since,  Chvostek's 
monograph  reviews  the  literature  up  to  1894. 

Etiology. — The  most  peculiar  feature  of  this  malady  is  the  appar- 
ently trivial  nature  of  the  exciting  causes  of  solution  of  the  red  cells. 
Slight  exposure  to  cold,  even  of  a  part  of  the  body,  has  been  the  most 
common  exciting  cause,  many  confirmed  subjects  being  able  to  induce 
an  attack  at  will.  Other  exciting  conditions  have  consisted  in  mental 
excitement  or  nervous  irritation,  and  muscular  or  nervous  exhaustion. 

In  recently  malarious  subjects  Tomasselli  and  Koch  have  placed  be- 
yond doubt  that  quinine  is  a  frequent  exciting  agent.  An  infectious 
origin  has  been  suggested  by  Layral  and  by  Cima.  The  underlying 
conditions  which  predispose  to  the  disease  are  known  to  include  only 
constitutional  syphilis  (Boas,  Gotze)  and  malaria  (Legg),  but  in  a  con- 
siderable proportion  of  cases  neither  of  these  factors  appears  to  exist. 

Pathogenesis. — That  a  vasomotor  neurosis  is  prominently  concerned 
in  the  solution  of  blood  cells  is  strongly  suggested  by  the  frequency 
with  which  nervous  influences  have  been  known  to  precipitate  the 
attack.  This  theory,  first  suggested  by  Dapper  in  1868,  has  been 
uniformly  maintained  up  to  the  present  time  by  the  majority  of  ob- 
servers. The  further  attempt  to  explain  the  destruction  of  blood  by 
this  means  has  as  yet  been  unsuccessful.  Chvostek  concluded  that  as 
a  result  of  malaria,  syphilis,  etc.,  the  red  cells  possess  diminished  re- 
sistance, not  to  cold  but  to  mechanical  traumatism,  and  that  when  the 
circulation  is  disturbed  by  vasomotor  contraction  of  peripheral  vessels 
the  fragile  red  cells  become  dissolved.  He  supported  his  view  by 
showing,  as  Dapper  had  done,  that  the  disturbance  of  circulation  fol- 
lowing ligation  of  a  finger  may  cause  solution  of  red  cells  in  the  ab- 
sence of  cold.  With  Pavy,  McKenzie,  Rosenbach,  and  others,  he 
attributed  to  the  kidney  a  special  importance  in  the  process.  Murri  ^ 
has  offered  evidence  to  show  that  the  red  cells  are  abnormally  suscep- 
tible to  the  effects  of  cold,  and  that  by  paralytic  dilatation  of  peripheral 
vessels  they  become  exposed  to  cold  and  dissolved.  But  Rodet  failed 
to  find,  by  experiment,  any  lack  of  resistance  of  the  red  cells  against 
cold,  and  numerous  cases  have  been  observed  to  follow  muscular  and 
mental  over-exertion.  (Fleischer,  Strobing.)  Ehrlich  supposes  that 
in  the  predisposed  subjects,  exposure  to  cold  causes  the  development  of 
"  ferments  "  which  dissolve  the  red  cells. 

Post-malarial  Hemoglobinemia. — The  relation  of  hlackwater  fevet^ 
to  malaria  has  been  the  subject  of  much  discussion,  the  opposing  views 
in  which  are  fully  presented  in  the  studies  of  Koch  and  of  Plehn. 
From  the  observations,  correlated  and  largely  contributed  by  these  ob- 
servers, it  is  evident  that  hemoglobinuria  arises  : 


318  HEMORRHAGIC  DISEASES  AND  HEMORRHAGIC  DIATHESIS. 

1 .  As  a  direct  result  of  the  action  of  the  malarial  parasite  upon  the 

blood. 

2.  As  an  immediate  effect  of  the  administration  of  quinine  on  pa- 
tients predisposed  to  hemoglobinemia  from  present  or  preexisting  ma- 
larial infection. 

3.  It  is  probable  that  hemoglobinuria  results  from  simple  exposure 
to  cold  or  to  other  exciting  agents,  in  subjects  who  have  acquired  the 
predisposition  through  previous  malarial  infection. 

Plehn  fully  demonstrates  that  blackwater  fever  may  occur  in  patients 
suffering  from  malaria,  without  the  administration  of  quinine,  and  with 
or  without  notable  exposure  to  any  of  the  ordinary  exciting  causes  of 
the  condition.  Numerous  cases  collected  or  observed  by  Plehn  leave 
this  fact  apparently  beyond  doubt. 

Plehn's  report  that  a  special  variety  of  parasite  is  concerned  in 
blackwater  fever  has  not  been  confirmed,  and  it  is  probable  that  the 
author  mistook  the  peculiar  appearance  of  granular  degeneration  of  red 
cells  for  minute  parasites.  The  most  extensive  changes  of  this  type 
observed  by  the  writer  were  seen  in  severe  malarial  cachexia  at  Mon- 
tauk  1898,  and  in  many  instances  the  altered  red  cells  presented  a  re- 
markable resemblance  to  corpuscles  infected  with  young  malarial  para- 
sites. 

On  the  other  hand  Koch  has  recently  drawn  contrary  conclusions 
from  a  thorough  study  of  41  cases.  He  finds  that  hemoglobinuria 
does  not  necessarily  follow  even  when  80  percent  of  the  red  cells  are 
infected  with  parasites.  The  great  majority  of  his  cases  developed  a 
few  hours  after  the  administration  of  quinine.  With  regard  to  the  re- 
lation of  malaria  to  blackwater  fever  he  found  that : 

(1)  Parasites  may  be  present  in  the  blood,  but  there  is  no  relation 
between  their  numbers  and  the  severity  of  the  hemoglobinuria. 
(2)  The  patient  may  have  suffered  from  malaria  some  weeks  or 
months  previously.  (3)  In  two  fatal  cases  in  the  tropics  he  found 
neither  parasites  in  the  blood  nor  pigment  in  the  viscera. 

Koch  concludes  that  life  in  the  tropics,  and  especially  malarial  in- 
fection, predispose  certain  individuals  to  hemoglobinuria,  but  that  the 
attack  is  invariably  excited  by  quinine,  or  occasionally  by  exposure  to 
cold  or  heat,  etc.  His  further  claim  that  no  cases  are  referable  to 
malaria  alone  cannot  be  accepted  in  the  face  of  the  observations  of 
Plehn  and  many  others,  of  fatalities  occurring  in  the  course  of  ma- 
larial infections  which  have  not  been  treated  by  quinine. 

Changes  in  the  Blood. — The  destruction  of  red  cells  very  promptly 
reduces  their  numbers  in  the  peripheral  circulation,  as  shown  by  the 
reports  of  numerous  observers.  Bristowe  and  Copeman  in  a  series  of 
attacks  induced  in  the  same  patient  found  a  maximum  loss  of  red  cells 
of  129,000  to  824,000.  In  an  idiopathic  case  of  moderate  severity 
Grawitz  found  a  loss  of  1. 13  millions  following  a  single  paroxysm.  Us- 
ually the  reduction  in  cells  is  not  so  marked,  and  Grawitz  has  explained 
this  fact  by  showing  that,  from  vasomotor  spasm  and  increased  diuresis 
during  the  attack,  the  blood  is  considerably  concentrated,  since  the  dry 


POST-MALARIAL  HEMOOLOBINEMIA.  319 

residue  of  the  blood  and  serum  is  considerably  increased  after  the 
seizure,  notwithstanding  the  loss  of  cells.  For  the  same  reason  and 
because  the  Hb  is  not  immediately  removed  from  the  serum,  the  per- 
centage of  Hb  is  not  excessively  low  during  or  immediately  after  the 
paroxysm.  Indeed  Frazer  found  an  increase  of  10  percent  of  Hb 
about  an  hour  after  the  beginning  of  an  attack.  Usually  there  is  a 
loss  of  5-10  percent.  Ponfick  claimed  that  at  least  one-sixtieth  part 
of  the  Hb  of  the  blood  must  be  lost  before  it  will  appear  in  the  urine. 

The  appearance  of  the  blood  in  the  stained  specimen  taken  shortly 
after  the  paroxysm  usually  gives  evidence  of  active  destruction  of 
blood.  The  red  cells  may  fail  to  form  rouleaux,  although  having  pos- 
sessed this  property  just  before  the  attack.  Many  very  pale,  or 
shrunken,  or  fragmented  cells  have  been  observed  in  some  cases,  while 
in  others  the  red  cells  were  found  to  contain  a  normal  amount  of  Hb. 
After  repeated  attacks  megalocytes  appear.  On  the  other  hand  Koh- 
ler  and  Obermayer  found  no  morphological  changes  in  a  case  losing 
650,000  red  cells  and  10  percent  Hb.  The  presence  of  polychromatic 
cells  or  of  granular  degeneration  of  red  cells  has  apparently  not  been  re- 
ported, but  in  a  case  of  blackwater  fever,  shortly  before  death,  the  writer 
found  the  latter  form  of  degeneration  in  extreme  degree.  Frank  noted 
in  a  paroxysmal  case  that  the  red  cells  in  the  fresh  condition  looked 
pale  and  brownish.  The  serum  has  been  found  distinctly  tinged  by 
the  dissolved  Hb.  Bristowe  and  Copeman  found  pigment  granules, 
crystals  of  Hb,  and  colorless  crystals  resembling  Charcot's. 

The  LEUCOCYTES  were  found  by  Frazer  moderately  increased  (21,- 
000),  but  the  majority  of  observers  have  reported  them  as  normal,  or 
if  above  normal,  as  being  little  affected  by  the  paroxysm.  The  blood 
plates  have  been  reported  as  very  much  increased  (Frazer,  Mesnet),  as 
seems  very  probable  from  the  extensive  destruction  of  red  cells. 

The  COAGULABILITY  OF  THE  BLOOD  is  normal  or  increased. 
Hayera '  noted  that  the  rapidly  formed  clot  softens  very  soon,  which 
Chvostek  finds  is  observed  in  other  conditions.  The  resistance  of  the 
red  cells,  as  determined  by  Hamburger's  method,  was  found  by  v. 
Hoff  to  have  fallen  to  38  percent  NaCl,  and  Sabrazes,  using  Malas- 
sez'  method,  also  found  it  reduced. 

Following  the  destruction  of  red  cells  there  is  usually  a  reduction 
in  the  alkalinity  op  the  blood,.  Robert  believes  this  to  be  due 
to  setting  free  of  phosphoric  and  glycerin-phosphoric  acids  during  the 
separation  of  oxyhemoglobin  from  the  red  cells. 

The  regeneration  of  the  blood  is,  in  uncomplicated  cases,  very 
prompt,  Bristowe  and  Copeman  finding  an  increase  of  500,000  cells 
after  5  days,  and  600,000  after  6  days.  Most  confirmed  cases,  how- 
ever, suffer  from  a  moderate  or  marked  grade  of  chronic  anemia, 
sometimes  associated  with  enlargement  of  the  spleen. 


320  HEMOBBHAOIC  DISEASES  AND  EEMOBBHAGIO  DIATHESIS. 

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I 


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21 


CHAPTER   XVIIL 
MISCELLANEOUS   CONSTITUTIONAL   DISEASES. 

DIABETES   MELLITUS. 

The  results  of  older  observers  led  to  conflicting  opinions  regarding 
the  condition  of  the  blood  in  diabetes,  since  it  appeared  that  in  cases 
of  about  equal  severity  the  Hb,  red  cells,  and  albumens,  might  in  one 
patient  be  increased  and  in  another  diminished,  or  might  vary  consider- 
ably at  different  times  in  the  same  patient,  not  infrequently  rising 
above  normal. 

The  studies  of  Henocque  were  among  the  first  showing  that  while 
individual  differences  may  be  considerable,  yet  in  a  series  of  cases  the 
Hb  does  not  vary  greatly  from  the  normal.  Leichtenstern,  finding  an 
excess  of  Hb  in  an  advanced  case  and  a  diminution  in  an  early  case, 
was  led  to  refer  the  anomaly  to  the  effects  of  diuresis  in  concentrating 
the  blood.  Although  the  extent  of  the  diuresis  depends  largely  upon 
the  amount  of  sugar  secreted,  a  very  close  relation  between  the  Hb  of 
the  blood  and  the  sugar  of  the  urine  has  not  apparently  been  estab- 
lished. Yet  the  above  logical  explanation  has  been  generally  accepted, 
and  the  marked  changes  observed  in  the  blood  of  many  diabetics  may 
be  referred  to  the  uncertain  balance  between  the  amount  of  water  ab- 
sorbed and  that  excreted  in  the  urine. 

In  the  late  stages  of  the  disease  other  factors  enter  to  further  dis- 
turb the  condition  of  the  blood.  General  failure  of  nutrition  belongs 
to  the  advanced  disease  and  the  blood  must  suffer  proportionately. 
Yet  even  in  extreme  cases  the  anaemia  is  commonly  masked  by  the 
concentration  of  the  blood  through  diuresis,  and  it  becomes  necessary 
to  class  the  blood  of  advanced  diabetes,  with  excess  of  Hb  and  cells, 
as  among  the  examples  of  oligemia  or  oligoplasmia. 

From  these  considerations  it  is  evident  that  the  estimation  of  Hb 
and  the  counting  of  red  cells  is  of  little  use  in  diabetes  unless  very 
carefully  controlled  by  reference  to  the  diet  and  urinary  excretion. 
Thus,  the  writer  found  in  an  emaciated  anemic  case  with  advanced 
phthisis,  78  percent  of  Hb  and  4,100,000  red  cells.  In  most  re- 
ported cases  in  which  the  daily  urine  measured  over  three  liters  the 
red  cells  approached  the  normal  figure. 

In  Grawitz's  case  of  coma  the  red  cells  rose  from  4.9  millions,  three 
weeks  previously,  to  6.4  millions  5  hours  after  the  onset  of  the  coma, 
and  the  dry  residue  of  the  blood  from  21.4  percent  to  24.75  percent. 
Possibly  the  result  was  in  part  referable  to  cyanosis.  Habershon  re- 
ports 3  cases  of  coma  with  excess  of  red  cells  (maximum  6.64  millions). 


DIABETES  MELLITUS. 


323 


They  all  suffered  from  dyspnea,  but  in  one  the  cells  were  lower  than 
they  were  a  week  before  death.  In  a  cyanotic  comatose  case  examined 
by  the  writer  there  were  6.8  million  red  cells. 

The  general  character  of  the  blood  in  diabetes  is  well  illustrated  in 
the  cases  reported  by  James,  as  follows  : 


No. 

Red  Cella. 

Hb. 

Specific  Gravity. 
Roy's  Method. 

1 

6.73 

66 

1.056 

2 

6.10 

61 

1.059 

3 

4.80 

58 

4 

5.25 

60 

5 

5.60 

65 

6 

3.55 

52 

1.054 

7 

52 

1.060 

8 

5.30 

75 

1.056 

9 

6.28 

108 

1.055 

10 

5.38 

96 

1.055 

11 

5.64 

112 

1.056 

12 

6.20 

112 

1.057 

13 

4.46 

55 

1.054 

14 

6.00 

96 

James  concluded  from  these  results  that  the  excess  of  red  cells  in 
diabetes  can  not  result  from  concentration  of  the  blood,  otherwise  the 
specific  gravity  would  have  been  higher.  Yet,  considering  the  per- 
centage of  the  Hb,  the  gravity  in  the  above  cases  is  distinctly  above  the 
usual  figure,  indicating  relative  anhydremia  with  marked  reduction  of 
Hb,  but  with  slight  loss  of  red  cells. 

The  leucocytes,  in  the  average  hospital  case  if  uncomplicated,  are 
normal,  subnormal,  or  moderately  increased.  In  7  of  20  untreated 
cases  Habershon  found  less  than  10,000  leucocytes,  in  the  others  a  leu- 
cocytosis  reaching  a  maximum  of  19,800,  and  being  rather  uniformly 
present  in  the  severer  cases.  With  the  advent  of  severe  symptoms  he 
found  the  leucocytes  to  increase,  and  in  three  cases  of  coma  there  was 
pronounced  leucocytosis  (maximum  28,500).  Cabot  found  no  leucocy- 
tosis  in  13  cases,  and  only  4,200  in  a  comatose  patient.  The  writer 
observed  leucocytosis  in  four  patients,  one  comatose,  but  autopsies  re- 
vealed phthisis,  suppuration,  or  pneumonia. 

Fat,  occurring  in  traces  in  normal  blood,  is  usually  increased  in  dia- 
betes and  may  become  extremely  abundant.  Usually  microscopical  ex- 
amination is  required  to  demonstrate  the  minute  extra-cellular  glob- 
ules in  specimens  stained  by  osmic  acid,  but  often  the  fat  rises  to  the 
surface  in  demonstrable  quantity  if  the  specimen  is  centrifuged  in  the 
hematokrit,  and  occasionally  the  blood  is  milky  from  the  abundance  of 
fat.  Its  origin  in  the  blood  is  not  understood,  but  v.  Noorden  says  that 
it  is  not  connected  with  a  previous  ingestion  of  fat,  as  is  the  case  with 
some  other  forms  of  lipemia. 

Chemistry. — The  chief  chemical  alteration  demonstrated  in  the  blood 
is  a  pronounced  increase  in  sugar.  While  normal  blood  contains 
.05— .15  percent  of  sugar,  Pavy  and  Seegen  have  found  as  much  as  .6 


324  MISCELLANEOUS  CONSTITUTIONAL  DISEASES. 

percent  in  severe  diabetes,  and  Frerichs  found  the  sugar  of  the  blood  to 
vary  between  .38-.44  percent,  while  that  of  the  urine  amounted  to 
5.5_8.4  percent,  Naunyn  obtained  .7  percent  in  the  blood  of  a  fatal 
case  in  which  the  urine  contained  4  percent.  In  Klemperer's  "  renal 
diabetes,"  the  sugar  of  the  blood  remains  normal.^ 

Henriques  and  Kolish  have  lately  claimed  that  an  excess  of  pre- 
formed sugar  exists  in  the  blood  only  in  alimentary  glycosuria,  while  in 
diabetes  the  preformed  sugar  of  the  blood  is  but  slightly  above  normal. 
They  find,  however,  that  in  diabetes  the  blood  contains  a  marked 
excess  of  jecorin  in  combination  with  albumens  which,  during  excre- 
tion, is  split  up  into  sugar  and  lecithin. 

Lepine  and  Barral  believe  that  diabetes  results  from  the  failure  of  a 
glycolytic  ferment  elaborated  by  the  pancreas  and  normally  present  in  the 
blood,  but  this  theory  has  not  been  demonstrated.  (See  Glycolytic 
Ferment.) 

Glycogen  in  the  blood  of  diabetes  has  been  demonstrated  in 
marked  cases  by  Gabritschewsky,  who  found  it  both  in  plasma  and 
leucocytes,  but  the  significance  of  the  brownish  extra-cellular  granules 
has  been  brought  into  question.  Livierato  could  find  but  little  glyco- 
gen in  the  plasma  and  none  in  the  leucocytes.  Futterer  claims  to  have 
demonstrated  in  the  brain  and  medulla  many  thrombi  composed  of 
glycogen.  Of  5  cases  of  diabetes  the  writer  found  in  each  a  few  leu- 
cocytes with  many  glycogen  granules,  while  in  the  plasma  were  brown- 
ish staining  granules  of  w^iich  the  significance  seemed  uncertain. 
The  glycogen-holding  leucocytes  were  less  abundant  than  in  cases  of 
pneumonia. 

Alkalinity. — The  alkalinity  of  the  blood  in  normal  subjects  varies 
between  300  and  400  mg.  of  NaOH  per  100  grms.  of  blood,  and  is 
always  diminished  in  patients  who  are  much  reduced  in  strength.  In 
diabetes  when  the  patients  are  suffering  little  general  disturbance,  the 
alkalinity  of  the  blood  has  been  found  to  be  very  slightly  reduced. 
(Minkowsky,  Kraus,  Lepine.)  When  diabetes  reaches  the  stage  of 
excretion  of  oxybutyric  acid  in  the  urine,  the  alkalinity  of  the  blood 
has  been  found  to  be  lower  than  in  any  other  known  condition,  falling 
as  low  as  40  mg.  of  NaOH  per  100  of  blood.  (Van  Noorden.)  In 
diabetic  coma,  Minkowsky  found  as  low  as  3.3  vol.  of  CO2  per  hun- 
dred of  blood. 

This  relative  acidemia  has  been  referred  to  the  presence  in  the  blood 
of  various  acid  products  of  proteid  metabolism,  /9-oxybutyric,  and  other 
fatty  acids.  These  acid  products  are  supposed  to  act  either  as  direct 
poisons,  or  indirectly,  by  lowering  the  alkalinity  of  the  blood.  The 
basis  of  this  theory  is  found  partly  in  the  demonstration  of  diminished 
alkalinity  in  the  blood,  but  largely  in  the  abundance  of  these  acids  or 
their  salts  in  the  urine. 

OBESITY. 

The  majority  of  healthy  obese  subjects  show  an  excess  of  Hb,  as  is 
clearly  indicated  by  the  extensive  observations  of  Kisch,  who  found  a 


ADDISON'S  DISEASE.  325 

notable  excess,  and  maximum  of  120  percent,  of  Hb,  in  79  of  100  fat 
subjects,  while  in  21  it  was  diminished,  reaching  55  and  60  percent  in 
some  instances.  The  existence  of  distinct  anemia  in  some  apparently 
healthy  fat  subjects  had  long  been  accepted,  but  the  opinion  was  ren- 
dered much  more  certain  by  Leichtenstern's  observation  of  four  such 
cases,  showing  considerable  reduction  of  Hb.  Oertel  also  found  an 
excess  of  5-8  percent  of  Hb,  and  Grawitz  reported  an  increase  of  the 
dry  residue  of  the  blood  in  very  fat  subjects.  It  appears,  therefore, 
that  there  is  a  distinct  tendency  toward  true  plethora  associated  with 
obesity,  while  the  anemia  occasionally  observed,  as  in  the  majority  of 
Kisch's  anemic  cases,  is  referable  to  other  causes. 

Grawitz,  in  two  cases,  observed  a  considerable  reduction  in  dry  resi- 
due both  of  the  whole  blood  and  of  the  serum,  as  a  result  of  a  course 
of  treatment  which  reduced  the  body  weight  10-12  lbs. 

That  the  plethora  of  obesity  is  sometimes  more  apparent  than  real 
is  suggested  by  the  constant  perspiration,  frequent  dyspnea,  and  ten- 
dency toward  venous  congestion,  from  which  these  subjects  suffer. 

ADDISON'S   DISEASE. 

Established  cases  of  this  disease  are  usually  attended  with  a  severe 
grade  of  anemia.  In  four  cases  reported  by  Tschirkoff  the  red  cells  be- 
fore treatment  numbered  from  2,733,000  to  3,280,000.  In  three  of 
Cabot's  cases,  and  in  three  examined  by  the  writer,  the  same  grade  of 
oligocythemia  was  observed,  while  Neumann  reported  more  severe 
anemia  with  1.12  million  red  cells  in  one  case.  Morphological  changes 
in  the  red  cells  are  not  marked,  but  microcytes  are  sometimes  quite 
abundant. 

Leucocytes  are  commonly  diminished,  sometimes  slightly  increased, 
and  are  subject  to  the  usual  variations  of  secondary  anemia.  Eosino- 
phile  cells  were  present  in  high  normal  proportions  in  Cabot's  and  in 
the  writer's  cases. 

Opposed  to  the  typical  cases  are  others  reported  in  which  the  red 
cells  were  in  excess  of  5  millions,  reaching,  in  Neumann's  observation, 
the  remarkable  figures  of  7.7  millions,  while  Tschirkoff  found  that  the 
Hb  in  early  cases  might  exceed  the  normal.  It  appears  likely  that 
disturbances  in  the  circulation  may  be  responsible  for  some  of  these 
anomalous  results,  but  the  subject  requires  further  observation. 

The  deposits  of  pigment  in  Addison's  disease  have  been  referred  by 
Riehl  and  Afanissiew  to  the  results  of  minute  thrombi  and  hemorrhages 
in  the  superficial  vessels,  and  Afanissiew  observed  the  disintegration 
of  red  cells  in  local  pigmented  areas,  v.  Kahlden,  however,  showed 
these  lesions  to  be  inconstant  and  probably  of  secondary  significance. 

An  interesting  contribution  to  the  pathology  of  Addison's  disease,  bearing 
on  this  point,  has  been  furnished  by  Tschirkoff,  who  examined  the  blood  of 
two  cases  with  special  reference  to  the  pigments,  by  means  of  Glan's  spec- 
trophotometric  method,  by  which  he  was  able  to  estimate  the  relative 
amounts  of  oxy-  and  reduced  Hb.     By  this  method  he  found  in  advanced 


326  MISCELLANEOUS  CONSTITUTIONAL  DISEASES. 

cases  a  much  greater  proportion  of  reduced  Hb  than  is  present  in  normal 
blood,  and  at  times  more  reduced  Hb  than  oxy-Hb.  During  improvement  he 
found  an  increase  in  the  proportion  of  oxy-Hb  at  the  expense  of  the  reduced 
Hb  but  without  coi-responding  increase  in  the  total  Hb  of  the  blood. 
He  found  evidence  pointing  to  the  presence  of  methemoglobin  in  the  blood, 
but  could  not  observe  any  quantitative  relation  between  these  changes  in  the 
Hb  of  the  blood  and  the  pigmentation  of  the  skin.  He  concluded  that  Addi- 
son's disease  is  associated  with  a  qualitative  rather  than  quantitative  change 
in  the  hemoglobin  of  the  blood,  with  a  corresponding  failure  to  furnish  oxy- 
gen to  the  tissues.     His  results  have  not  yet  been  verified. 

GOUT. 

From  the  comparatively  few  recorded  observations  it  is  evident  that 
acute  gout  has  little  eiFect  upon  the  red  cells  and  Hb  of  the  blood,  in 
which  respect  it  differs  from  acute  rheumatism.  In  chronic  gout,  also, 
Duckworth  found  cases  with  inappreciable  anemia  and  concluded  that 
when  the  disease  is  associated  with  anemia,  the  condition  of  the  blood 
is  referable  principally  to  complications  such  as  hemorrhage,  nephritis, 
lead  poisoning,  bad  hygiene,  etc.  The  writer  found  uniform  but  mod- 
erate anemia  in  a  series  of  chronic  cases  examined  at  Roosevelt  Hos- 
pital, the  patients  all  coming  from  the  poorer  classes. 

The  leucocytes  are  probably  increased  in  acute  attacks,  but  there  are 
apparently  no  direct  observations  on  this  point.  In  the  chronic  cases 
leucocytosis  of  moderate  grade  may  be  observed,  but  it  is  difficult  to 
determine  its  relation  to  the  gouty  process,  as  many  of  these  patients 
suffer  from  other  complaints.  Neusser  '  mentions  the  usual  presence 
of  mixed  leucocytosis  in  a  series  of  100  cases  of  the  uric  acid  diathesis. 

Chemistry. — The  chemistry  of  the  blood  in  gout  has  for  many  years 
been  the  subject  of  extensive  investigation  and  while  the  presence  of 
abnormal  principles  has  been  demonstrated,  an  important  relation  of 
these  principles  to  the  pathogenesis  of  the  disease  has  not  been  estab- 
lished. 

Garrod  first  demonstrated  an  excess  of  uric  acid  in  the  shed  blood, 
finding  .025—175  grains  of  uric  acid  for  1,000  grains  of  serum,  in  five 
cases  during  and  shortly  after  the  attack,  and  this  uricacidemia  has  been 
noted  by  Salomon,^  v.  Jaksch,  and  Klemperer.'  Recently  Magnus- 
Levy  ^  failed  to  find,  in  several  cases,  any  constant  variations  in  the 
amount  of  uric  acid  which  might  be  regarded  as  an  increase. 

Garrod  perfected  a  ready  clinical  method  for  the  demonstration  of 
uric  acid  in  the  blood  or  serum  of  gouty  patients,  commonly  known  as 
the  '*  thread  test." 

One  to  two  drams  of  serum  from  fresh  blood  drawn  from  a  vein  are 
placed  in  a  broad,  flat  dish,  about  3  inches  in  diameter  and  +  inch  deep,  and 
to  it  are  added  6  minims  33-percent  acetic  acid  to  each  dram  of  serum.  A 
couple  of  old  but  clean  linen  threads  are  submerged  in  the  fluid  and  the  ves- 
sel is  allowed  to  partially  evaporate  at  room  temperature  for  36-60  hours, 
when  the  threads  will  be  found  to  have  gathered  minute  crystals  of  uric  acid, 
if  any  considerable  trace  is  present  in  the  blood.  They  may  be  washed  in 
water  and  freed  from  any  adherent  phosphate  and  identified  under  the  mi- 
croscope.    Garrod  found  that  crystals  begin  to  deposit  on  the  thread  when 


OSTEOMALACIA.  327 

the  serum  contains  .025  gr.  of  uric  acid  per  1,000,  and  become  very  numerous 
with. 08  gr.  per  1,000.  The  test  must  be  carefully  performed  and  may  fail, 
especially  from  too  rapid  or  prolonged  evaporation  or  from  heating  above 
75°  F.  Serum  obtained  from  a  blister  may  be  used,  but  not  when  obtained 
from  the  neighborhood  of  an  inflamed  joint. 

Excess  of  uric  acid  in  the  blood  is  not,  however,  pathognomonic  of 
gout,  being  absent  in  some  undoubted  cases  (Duckworth),  and  being 
abundantly  present  in  many  other  conditions,  such  as  pneumonia  (Sal- 
omon),^ and  other  conditions  with  leucocytosis,  emphysema,  nephritis, 
severe  anemia  (v.  Jaksch  ^),  leukemia  (Magnus-Levy),^  and  after  a 
diet  rich  in  nucleo-proteids  (Weintraud). 

Alkalinity. — The  assumption  by  Garrod  that  an  excess  of  uric  acid 
in  the  blood  is  associated  with  diminished  alkalinity  has  not  been  sup- 
ported by  late  observations.  Klemperer,^  estimating  the  alkalinity  by 
the  content  of  the  blood  in  CO2,  found  no  distinct  variations  from  the 
normal  in  three  cases  during  the  attack.  Luff,  using  Wright's  method, 
also  failed  to  find  any  loss  of  alkalinity  during  the  course  of  an  acute 
attack,  and  Magnus-Levy,  using  Lowy's  method,  failed  to  find  any  con- 
stant variations  in  a  series  of  16  cases  examined  at  various  periods. 

From  the  recent  studies  of  the  chemistry  of  the  blood  in  gout,  it  is 
evident  that  Garrod's  theory  of  the  nature  of  the  disease  must  be 
abandoned. 

OSTEOMALACIA. 

The  usual  condition  of  the  blood  in  osteomalacia  appears  to  be  that 
of  moderate  chlorotic  anemia.  Such  cases  are  reported  by  Eisenhart, 
Tschistowitch,  and  others,  while  Seligman,  in  an  advanced  case,  found 
41  percent  of  Hb. 

The  red  cells  are  usually  normal  or  very  slightly  reduced.  Shortly 
after  abortion  Tschistowitch's  case  showed  3.1  million  cells,  but  the 
numbers  increased  rapidly,  later  to  oscillate  between  3.4  and  6.8  mil- 
lions.   One  of  Rieder's  cases  had  3.8  million  cells,  another  4.9  millions. 

The  leucocytes  have  varied  from  subnormal  to  moderately  increased 
numbers.  The  lymphocytes  are  usually  very  numerous,  an  excessive 
proportion  (maximum  56  percent)  having  been  found  by  Tschistowitch, 
while  Ritchie  observed  moderate  lymphocytosis.  Myelocytes  have 
been  found  by  Neusser  and  by  Tschistowitch. 

Neusser  ^  proposed  to  divide  cases  of  osteomalacia  into  two  groups, 
one  showing  myelocytes  in  the  blood,  the  other  showing  high  propor- 
tions of  eosinophile  cells,  of  which  he  had  seen  examples.  High 
normal  proportions  of  eosins  have  been  found  by  several  observers,  but 
not  by  others,  viz.,  Fehling,  Sternberg,  and  Chrobak,  who  were  prob- 
ably looking  for  a  distinctly  abnormal  number.  In  Tschistowitch's 
case  their  numbers  varied  greatly  during  the  year  over  which  his  ob- 
servations extended. 

Chemistry. — The  alkalinity  usually  varies  between  normal  limits 
(Limbeck)  but  has  been  found  both  increased  and  diminished.  Lactic 
acid  has  never  been  fully  demonstrated  in  the  blood.     Peters  claimed 


328  MISCELLANEOUS  CONSTITUTIONAL  DISEASES. 

to  have  found  in  the  blood  a  nitrifying  micro-organism,  cultures  of 
which  produced  in  dogs  a  condition  resembling  osteomalacia.  This 
claim  has  not  been  established. 

RACHITIS. 

The  state  of  the  blood  in  rachitis  varies  with  the  extent  and  sever- 
ity of  the  primary  disease  and  is  markedly  affected  by  complications. 
Nearly  all  series  of  cases  reported  contain  some  examples  of  pro- 
nounced rachitis  in  which  the  red  cells  were  nearly  normal  and  the  Hb 
very  moderately  reduced,  and  some  observers,  as  Felsenthal  and 
Morse,  did  not  meet  with  severe  anemia  in  any  case.  Nor  does  it  ap- 
pear that  the  anemia  bears  a  very  close  relation  to  the  extent  of  the 
disease,  although  as  a  general  rule  the  advanced  cases  with  enlarge- 
ment of  the  spleen  show  greater  anemia  than  do  those  without  involve- 
ment of  the  viscera.  (Monti,  Berggrun.)  It  is  agreed  on  all  sides 
that  the  disease  is  not  associated  with  any  peculiar  type  of  anemia,  al- 
though the  hyperemia  of  the  bone  marrow  might  be  expected  to  yield 
an  unusually  large  number  of  nucleated  red  cells.  Yet  these  cells  are 
apparently  not  more  abundant  in  rickets  than  in  congenital  syphilis 
(Monti),  while  Gundobin  found  the  same  grade  and  type  of  anemia  in 
rachitic  as  in  other  poorly  developed  infants.  Rachitis  figures  about 
equally  with  syphilis,  etc.,  in  the  etiology  of  v.  Jaksch's  anemia. 

The  existence  of  rachitis  in  patients  with  normal  blood  raises  a  question 
as  to  the  cause  of  the  anemia  usually  found  in  the  disease,  and  the  conclu- 
sion seems  justified  that  the  anemia  of  rickets  is  largely  referable  to  the  gen- 
eral malnutrition  of  the  patient  and  to  a  variety  of  complications,  especially 
gastroenteritis.  Moreover  the  pathological  nature  of  the  disease  renders  it 
extremely  improbable  that  the  lesion  in  itself  has  very  marked  effect  upon 
the  blood.  So  far  as  our  present  knowledge  goes,  the  anemia  of  rickets  is 
practically  that  of  marasmus  and  gastroenteritis. 

Simple  chlorotic  anemia  is  the  usual  condition  of  the  blood  of  rachitic 
children.  No  other  forms  were  encountered  among  the  cases  of 
Felsenthal  and  Morse,  most  of  which  were  described  as  of  moderate 
grade ;  and  a  few  examples  of  the  same  type  have  been  described  by 
others.  Although  the  red  cells  may  be  above  5  millions,  the  Hb  is 
invariably  reduced,  the  color-index  frequently  falling  as  low  as  in 
primary  chlorosis.  Morse  found  an  average  Hb-index  of  .7,  and 
Felsenthal  obtained  only  50  percent  of  Hb  in  one  case  with  over  5 
million  cells.  The  usual  morphological  changes  in  the  red  cells  are  to 
be  observed,  and  a  few  nucleated  red  cells  are  nearly  always  to  be  found 
in  the  young  subjects.  The  leucocytes  in  cases  with  mild  anemia  are 
usually  found  at  the  higher  normal  limits  or  distinctly  increased. 
Rickets  does  not  appear  among  Monti's  cases  of  simple  anemia  with- 
out leucocytosis. 

Grave  secondary  anemia  is  observed  in  many  cases  of  rachitis  in 
which  there  are  almost  always  some  serious  complications.  Although 
the  progress  of  rachitic  anemia  is  sometimes  moderately  rapid,  the  cause 


RACHITIS.  329 

of  the  destruction  of  red  cells  is  not  always  apparent,  v.  Jaksch  saw 
the  red  cells  fall  from  1.6  millions  to  750,000  within  three  months, 
while  Luzet  saw  a  reduction  of  500,000  cells  in  three  weeks.  Usually 
the  loss  of  cells  occurs  more  slowly,  and  in  the  grave  forms  of  anemia 
the  impoverishment  of  the  blood  is  usually  attended  with  enlargement 
of  the  spleen,  and  often  of  the  liver. 

The  changes  in  the  red  cells  are  then  similar  to  those  of  other  forms 
of  severe  secondary  anemia  of  chronic  course,  but  poikilocytes  and  nu- 
cleated red  cells  are  unusually  numerous.  The  Hb-index  varies.  In 
a  few  instances,  especially  those  of  more  rapid  course,  the  Hb  is  defi- 
cient, but  usually  the  Hb-iudex  rises  and  may  become  abnormally 
high.  Thus,  Monti  and  Berggrun  found  50-55  percent  Hb  with  2.35 
million  cells.     In  all  cases  of  this  type  there  is  leucocytosis. 

Progressive  pernicious  anemia  appears  to  be  a  relatively  infrequent 
complication  of  rickets.  In  11  cases  of  pernicious  anemia  in  young 
children  or  infants,  collected  by  Monti  and  Berggrun,  rickets  existed 
or  was  mentioned  in  only  two,  and  one  of  these  was  complicated  by 
congenital  syphilis.  The  writer  has  had  a  similar  experience,  never 
having  found  the  well-marked  characters  of  progressive  pernicious 
anemia  in  a  rickety  child. 

Leucocytes. — It  has  already  been  shown  that  in  many  mild  cases  of 
rickets  the  leucocytes  do  not  exceed  the  normal  limits  for  young  in- 
fants. The  slight  excess  over  10,000  seen  in  most  of  the  mild  cases 
reported  is  not,  as  Cabot  points  out,  abnormal  for  infants.  Felsenthal 
found  30,000  white,  with  4  million  red  cells,  in  one  mild  case  in  which 
no  complication  was  noted. 

In  the  severer  cases  leucocytosis  is  nearly  constant,  but  does  not 
usually  exceed  30,000.  Yet  Luzet  believes  that  there  are  all  grades  of 
the  leucocytosis  of  rickets  up  to  that  of  leukemia,  where  it  is  certainly 
difficult  at  times  to  distinguish  the  leucocytosis  of  a  rachitic  anemia  from 
that  of  v.  Jaksch's  anemia.  The  lymphocytes  are  usually  quite  numer- 
ous, but  not  often  excessive  for  the  age.  Morse  found  an  average  of 
43  percent  of  lymphocytes  in  twenty  rachitic  children  under  two  years 
of  age.  Distinct  lymphocytosis  was  observed  by  Rieder,  Weiss,  Monti 
and  Berggrun,  and  Morse,  and,  while  probably  not  uncommon  in 
young  subjects,  is  without  special  significance. 

Eosinophile  cells  are  often  relatively  numerous.  Morse  found  an 
average  of  3  percent.  They  may  be  distinctly  increased,  as  Hock  and 
Schlesinger  found  20  percent  in  one  subject  and  Weiss,  16  percent  in 
another,  or  they  may  be  scanty.     (Rieder,  Cabot.) 

The  conditions  leading  to  excess  of  leucocytes  in  rickets  are  not  well 
understood.  Limbeck  refers  the  excess  principally  to  the  co-existent 
gastro-enteritis  which  is  often  present.  Whilst  most  cases  with  leu- 
cocytosis show  hyperplastic  splenitis,  these  two  conditions  are  most 
probably  separate  effects  of  a  common  cause.  Not  all  cases  with  en- 
larged spleen  show  leucocytosis,  which  is  commonly  absent  in  pro- 
nounced cases  of  "  splenic  anemia  "  in  infants.  Luzet,  however,  con- 
nects the  excess  of  leucocytes  with  the  hyperplasia  of  the  spleen. 


330  MISCELLANEOUS  CONSTITUTIONAL  DISEASES. 

It  seems  not  improbable  that  the  hyperemia  of  the  marrow  may  tend 
to  discharge  an  unusual  number  of  white  cells  into  the  circulation,  a 
possibility  which  is  favored  also  by  the  large  number  of  nucleated  red 
cells  commonly  seen,  by  the  frequent  presence  of  a  few  leucocytes  with 
mitotic  nuclei'  (Hock,  Schlesinger),  and  by  the  nearly  constant  occur- 
rence of  myelocytes. 

Chemistry. — The  specific  gravity  of  the  blood  was  reduced  in  pro- 
portion to  the  loss  of  Hb  in  the  cases  of  Hock  and  Schlesinger.  Even 
in  patients  who  appeared  otherwise  in  good  health  the  specific  gravity 
of  the  blood  was  distinctly  reduced  in  12  cases  examined  by  Felsenthal 
and  Bernhard. 

MYXEDEMA. 

The  anemia  of  myxedema,  in  the  majority  of  pronounced  and  un- 
treated cases,  is  of  the  secondary  chlorotic  type,  with  slight  leucocy- 
tosis,  and  of  moderate  grade.  Bramwell  observed  well  marked  anemia 
in  26  of  33  cases.  Of  23  cases  collected  by  Murray  the  blood  was 
normal  in  7,  while  in  the  cases  of  Cabot  and  in  those  of  Kraepelin  there 
was  no  anemia.  The  most  severe  anemia  recorded  was  that  of  Le 
Breton's  case,  in  a  child  of  three  years,  with  1.7  million  cells,  65  per- 
cent of  Hb,  and  4,500  leucocytes.  Many  other  cases  have  shown  a 
reduction  of  the  red  cells  to  about  3  millions  (Bramwell,  Putnam,  and 
2  cases  of  the  writer's).  Kraepelin  noted  by  careful  measurements  a 
distinct  increase  in  the  diameters  of  the  red  cells  in  4  cases,  and  claimed 
this  feature  to  be  one  of  the  typical  symptoms  of  myxedema.  The 
chemical  examinations  of  the  blood  of  these  patients  supported  this 
conclusion,  by  showing  excess  of  solids.  Le  Breton  also  noted  a  sim- 
ilar condition  in  the  blood  of  his  case  but  the  patient  was  very  anemic 
(1.7  million  cells).  Cabot  failed  to  find  any  such  changes  in  the  red  cells 
of  three  cases.  When  present  it  is  probably  referable  to  the  increased 
venosity  of  the  blood  which,  according  to  Horsley,  is  commonly  pres- 
ent in  myxedema.  The  Hb  is  usually  moderately  reduced,  but  less 
than  in  most  other  forms  of  secondary  anemia.  In  Le  Breton's  case 
the  Hb-index  was  abnormally  high  (L8),  but  since  large  nucleated  red 
cells  were  present  the  condition  of  the  blood  seems  to  accord  with  that 
of  pernicious  anemia. 

In  two  of  Kraepelin's  cases,  while  the  Hb  by  Fleischl's  method  was 
not  excessive  (5.4,  5.6  million  cells,  93-98  percent  Hb),  by  the 
spectrophotometric  method  an  abnormal  quantity  of  blood  pigment  was 
demonstrated.  The  specific  gravity  was  also  abnormally  high.  In 
several  other  cases,  even  when  the  red  cells  were  considerably  deficient, 
the  Hb-index  was  normal  or  increased.  (Bramwell.)  Putnam  re- 
ports a  few  myelocytes  in  one  case  in  which  the  blood  was  otherwise 
nearly  normal. 

Thyroid  treatment  has  usually  been  followed  by  marked  improvement 
in  the  blood.  In  6  weeks  Kraepelin's  case  gained  700,000  red  cells, 
and  nucleated  red  cells  and  leucocytes  disappeared.  Putnam  observed 
polythemia  (5.7  millions)  after  6  months'  treatment.     Marked  anemia 


BIBLIOGRAPHY.  331 

followed  the  administration  of  over-doses  of  thyroid  extract  in  one  of 
Bramwell's  cases,  but  on  smaller  doses  the  patient  did  well.  The 
course  of  the  blood  changes  in  this  case  was  as  follows  : 

Red  cells.  Hb. 

October  28  (before  treatment) 3.8  millions.  65  percent. 

November  28  (after  acute  thy roidism) 2.6        "  54        " 

December  21  (smaller  doses) 3.8        "  68        " 

January  13 4.3        "  70        " 

Leucocytes  are  usually  not  increased,  but  in  6  of  Murray's  23  cases 
there  was  leucocytosis.  In  uncomplicated  cases  without  severe  anemia 
it  appears  to  be  nearly  always  absent.  The  proportions  of  the  various 
leucocytes  are  not  altered.  Cabot  found  5  and  4.4  percent  of  eosins  in 
two  cases,  but  Schmidt  found  only  1.5  percent  of  these  cells.  Putnam 
reports  a  few  myelocytes  in  one  case  in  which  the  blood  was  otherwise 
nearly  normal. 

Chemistry. — Very  numerous  and  elaborate  studies  of  the  chemistry 
of  the  blood  in  myxedema,  and  especially  in  thyroidism,  have  failed 
as  yet  to  demonstrate  the  exact  nature  of  this  peculiar  toxemia.  Halli- 
burton in  1885  demonstrated  mucin  in  the  blood  of  thyroidectomized 
dogs,  an  observation  which  has  been  fully  confirmed,  and  Levine  has 
recently  produced  peculiar  chronic  toxemia  by  injection  of  mucin  in 
animals  after  partial  thyroidectomy,  although  similar  injections  in 
healthy  animals  were  innocuous.  Yet  in  the  human  subject  an  excess 
of  mucin  in  the  blood  has  not  been  demonstrated. 

The  chemical  analysis  of  Kraepelin's  cases,  by  Schneider,  showed  the 
exaggerated  effects  of  chronic  venosity  of  the  blood,  a  condition  first 
noted  clinically  in  myxedema  by  Horsley.  Here  there  was  considerable 
increase  in  specific  gravity  of  the  blood  (1.0625-1.0636)  and  of  the 
serum  (1.0317-1.0329),  while  the  dry  residue  of  whole  blood,  serum, 
and  red  cells  was  also  increased. 

Bibliography. 

Constitutional  Diseases. 

Afanissiew.     Cited  by  Tschirkofl' (Russian). 

Arthus.     Archiv  de  Physiol.,  T.  24,  p.  337. 

Bramwell.     Anemia. 

Chrobak.     See  Fehling. 

Duckworth.     Treatise  on  Gout,  London,  1890. 

Eisenhart.     Deut.  Archiv  Klin.  Med.,  Bd.  49,  p.  181. 

Fehling.     Zeit.  f.  Geburtsh.,  Bd.  30,  p.  471. 

Felsenthal.     Archiv  f.  Kinderheilk.,  Bd.  17,  p.  333. 

Frerichs.     Diabetes,  Berlin,  1884. 

Futterer.     Verh.  d.  ph.  med.  Gesell.,  Wurzburg,  1888,  p.  112. 

Gabriischewsky.     Archiv  f.  exper.  Path.,  Bd.  28,  p.  272. 

Garrod.     Gout  and  Rheumatic  Gout,  London,  1876,  p.  80. 

Gundobin.     Jahrb.  f.  Kinderheilk.,  1893,  Bd.  35,  p.  187. 

Hahershon.     St.  Barthol.  Hosp.  Rep.,  1890,  p.  152. 

Halliburton.     Cited  by  Horsley. 

Henriques.     Zeit.  f.  Physiol.  Chemie,  Bd.  26. 

Hock,  Schlesinger.     Beitrage  zur  Kinderheilk.,  Wien,  1892. 

Horsley.     Brit.  Med.  Jour.,  1885,  I.,  p.  419. 

V.  Jaksch.     iZeit.  f.  Heilk.,  1890,  p.  415. 

James.     Edin.  Med.  Jour.,  1896,  Vol.  62,  p.  93. 


332  MISCELLANEOUS  CONSTITUTIONAL  DISEASES. 

V.  Kahlden.     Vircliow's  Archiv,  Bd.  114,  p.  112. 

Kisch.     Zeit.  f.  klin.  Med.,  Bd.  12. 

Klemperer.  'Deut.  med.  Woch.,  1895,  No.  40.  ^Untersuch.  u.  Gicht.,  Berlin, 
1896.     "Deut.  med.  Woch.,  1896,  p.  46. 

Kolish,  Stejskal.     Wien.  klin.  Woch.,  1897,  p.  1101. 

Kraepelin.     Deut.  Archiv  klin.  Med.,  Bd.  49,  p.  587. 

Kraus.     Archiv  f.  Heilk.,  1889,  p.  106. 

Krypiakiewiez.     Wien.  med.  Woch.,  1892,  No.  25. 

Le  Breton.     Bull.  Soc.  des  Hop.,  1895,  p.  22. 

Leichtenstern.     Untersuch.  u.  d.  Hmglb'n,  1878. 

Lepine.     Kevue  de  Med.,  1887,  p.  224.     Lyon  Med.,  T.  62,  p.  619  ;   T.  63,  p.  83. 

Lepine,  Barral.     Lyon  Med.,  T.  62,  p.  619  ;  T.  63,  p.  83. 

Levine.     Proc.  N.  Y.  Path.  Soc,  1900. 

Livierato.     Deut.  Archiv  klin.  Med.,  Bd.  53,  p.  303. 

Luff.     The  Pathology  of  Gout,  London,  1898. 

Luzet.     Etude  sur  les  Anemies  de  I'Enfance,  Paris,  1891. 

Magnus-Levy.  'Zeit.  f.  klin.  Med.,  Bd.  36,  p.  366.  ^Virchow's  Archiv,  Bd.  152, 
p.  107. 

Minkowsky.  Archiv  f.  exper.  Path.,  1884,  Bd.  18,  p.  35.  Berl.  klin.  Woch.,  1892, 
No.  5. 

Monti,  Berggrun.     Chronische  Anemie  d.  Kindesalter,  1893. 

Morse.     Boston  Med.  Surg.  Jour.,  Vol.  136,  p.  369. 

Murray.     20th  Cent.  Practice,  IV.,  p.  710. 

Naunyn.     Nothnagel  Spec.  Path.,  Bd.  7,  Th.  6,  p.  150. 

Neumann.     Deut.  med.  Woch.,  1894,  p.  105. 

Neusser.     'Wien.  klin.  Woch.,  1892,  p.  41.     nVien.  klin.  Woch.,  1894,  p.  727. 

V.  Noorden.     20th  Cent.  Practice,  Vol.  II.,  p.  99. 

Oertel.     Allgem.  Ther.  d.  Krieslauf st. ,  Leipsic,  1891,  p.  36. 

Pavy.     Lancet,  1878,  I.,  p.  557. 

Peters.     Rif.  Med.,  1892,  No.  78,  pp.  119,  163. 

Putnam.     Amer.  Jour.  Med.  Sci.,  1893,  Vol.  106,  p.  125. 

Biehl.     Zeit.  f.  klin.  Med.,  Bd.  X. 

Ritchie.     Edin.  Med.  Jour.,  1896,  Vol.  42,  p.  208. 

Salomon.    •  Charit^-Annalen,  1880,  V.,  p.  137.    "Zeit.  f.  physiol.  chemie,  1878,  p.  65. 

Seegen.     Diabetes  Mellitus,  Berlin,  1893. 

Seligman.     Cent.  f.  Gyn.,  1893,  pp.  374,  649. 

Sternberg.     Zeit.  f.  klin.  Med.,  Bd.  22,  p.  265. 

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Tschistowitch.     Berl.  klin.  Woch.,  1893,  p.  919. 

Weintraud.     Deut.  med.  Woch.,  1895,  V.  B.,  p.  185. 

Weiss.     Jahrb.  f.  Kinderheilk. ,  Bd.  35,  p.  146. 


! 


I 


CHAPTER  XIX. 

NERVOUS  AND  MENTAL  DISEASES. 

MANIA,  GENERAL  PARESIS,  MELANCHOLIA,  DEMENTIA, 

EPILEPSY. 

The  blood  of  inmates  of  insane  asylums  has  been  the  subject  of 
much  careful  study. 

In  1873  Sutherland  examined  the  blood  of  149  insane  patients, 
finding  in  4  of  them  grave  secondary  anemia  with  leucocytosis.  Ex- 
cess of  leucocytes  occurred  in  many  other  milder  or  earlier  cases. 

McPhail  contributed  the  first  scheme  of  the  blood  changes  in  gen- 
eral paresis  finding  from  a  study  of  fifteen  cases  that : 

1.  The  Hb  was  moderately  low  on  admission  (62.70  percent),  im- 
proved for  a  time,  owing  to  the  better  hygienic  conditions  prevailing 
in  the  institutions,  but  fell  (52.66  percent)  in  the  terminal  stages  of  the 
disease.  (2)  The  red  cells  diminished  steadily  with  the  progress  of  the 
disease,  reaching  in  one  case  3.4  millions.  (3)  Leucocytosis  (minimum 
12,700)  was  noted  in  all  cases,  progressed  with  the  disease  and  reached 
a  well-marked  grade  in  the  terminal  stages,  27,700  to  36,600. 

Lewis,  Steele,  Seppili,  and  others  obtained  results  very  similar  to 
the  above  and  added  many  new  details.  Smyth  examined  the  blood 
in  cases  of  melancholia,  epilepsy,  general  paresis,  and  secondary  de- 
mentia. He  found  the  red  cells  as  a  rule  below  the  normal,  while  the 
Hb  was  reduced  in  much  greater  degree.  The  average  results  ob- 
tained were  as  follows : 


Cases. 

Hb?(. 

Red  cells. 

S.  G. 

During 
ConTuIsions. 

Melancholia 

10 
50 
40 
12 

69.7 
62.8 
68.7 
53.7 

4. 684  mil. 
4.520   " 
4.700    " 
4.070    " 

1.0572 
1.0568 
1.0605 
1.0612 

EuileDsv 

1.0596 

General  paresis 

Secondary  dementia 

The  more  marked  anemia,  with  high  specific  gravity,  of  secondary 
dementia,  and  the  increase  of  specific  gravity  after  epileptic  convulsions, 
which  was  not  invariable,  are  specially  worthy  of  note. 

Winckler  also  found  a  distinct  loss  of  Hb,  especially  in  the  depressed 
forms  of  insanity.  Paroxysms  of  mania  or  of  melancholia  caused  a 
loss  of  both  cells  and  Hb,  which  was  restored  after  the  recovery  from 
the  attack.  Terminal  dementia  was  associated  with  a  progressive 
anemia.  Capps  examined  12  cases  of  general  paresis  in  which  the  red 
cells  never  fell  below  four  while  never  reaching  five  millions  (average 


334  NERVOUS  AND  MENTAL  DISEASES. 

4.789  millions).  The  Hb  varied  between  73.92  percent  (average  85  per- 
cent), and  the  specific  gravity  between  1.058-1.066.  Convulsions  ap- 
peared to  concentrate  the  blood.  JelliiFe,  working  at  the  Binghampton 
State  Hospital,  altitude  400  meters,  found  moderate  polycythemia  in 
14  of  17  cases,  but  the  Hb  was  usually  reduced,  in  one  case  to  52  per- 
cent. The  specific  gravity  ranged  from  1.047  to  1.060.  Langdon  and 
Bamford,  at  the  Hudson  River  State  Hospital,  obtained  in  a  reasonably 
short  time  20  very  anemic  cases  of  melancholia,  with  red  cells  between 
2-3  millions,  Hb  between  60-85  percent.  Treatment  by  bone  mar- 
row rapidly  improved  the  condition  of  the  blood.  Severe  anemia,  red 
cells  2.5  millions,  Hb  25  percent,  is  also  reported  by  Howard  in  a  case  of 
terminal  dementia,  while  in  Steele's  35  cases  of  melancholia  the  aver- 
age of  red  cells  was  3  millions,  of  Hb,  75  percent. 

The  Leucocytes. — In  early  cases  there  is  usually  no  leucocytosis, 
and  the  uniform  tendency  to  leucocytosis  observed  by  McPhail  has  not 
been  found  by  all  subsequent  observers.  Smyth  reported  an  excess  in 
many  cases  but  without  relation  to  the  symptoms  of  the  disease. 

Most  of  Capps'  patients  had  leucocytosis,  as  did  also  the  very  anemic 
subjects  examined  by  Langdon  and  Bamford,  while  in  the  tables  of 
Jelliffe  and  Somers,  leucocytosis  was  absent  in  the  majority  of  cases. 
Leucocytosis  is  more  frequent  when  there  is  anemia,  in  the  last  stages 
of  the  disease,  and  it  has  been  found  rather  more  frequent  in  the  more 
acute  forms  of  insanity  and  in  terminal  dementia.  Somers  found  an 
average  of  8,315  leucocytes  in  19  cases  of  mania,  7,947  in  19  cases 
of  melancholia,  10,473  in  19  cases  of  dementia,  and  8,800  in  5  cases 
of  general  paresis.  In  16  cases  of  epilepsy  Kohlmann  obtained  dis- 
tinct leucocytosis  in  only  one  (14,000).  Pease  followed  the  leucocy- 
tosis long  enough  to  show  that  it  is  often  transitory. 

The  proportions  of  the  various  forms  of  leucocytes  show  no  constant 
or  significant  variations.  When  the  total  numbers  are  increased  the 
polynuclear  forms  are  usually  most  affected.  Lymphocytosis  is  fre- 
quently observed,  especially  in  epilepsy.  The  eosins  show  irregular 
variations,  being  absent  in  some  cases,  reaching  high  normal  figures  in 
others,  while  Roncorini  found  a  marked  excess,  up  to  25  percent,  in 
maniacal  cases.  Krypiakiewicz  also  found  an  increase  of  eosins  in  the 
more  acute  forms  of  insanity,  and  comparatively  low  proportions  in  the 
chronic  forms.  Capps  could  not  find  that  the  restlessness  of  the  pa- 
tient was  always  connected  wnth  any  increase  in  eosins. 

To  recapitulate  the  results  of  the  above  studies,  it  has  been  shown 
that  the  common  forms  of  insanity  may  develop  in  an  anemic  subject 
or  in  one  whose  blood  is  normal.  The  disease  may  run  its  course 
without  anemia,  but  usually  the  state  of  the  blood  accords  with  the 
general  state  of  nutrition.  In  some  cases,  especially  of  melancholia, 
the  blood  suffers  more  than  the  general  nutrition. 

Leucocytosis  is  frequently  observed,  especially  in  anemic  subjects,  in 
late  stages,  and  after  convulsions.  Convulsions  may  concentrate  the 
blood  and  induce  leucocytosis.  Acute  mania  is  not  associated  with 
any  specific  changes  in  the  morphology  of  the  blood. 


CHOREA.  335 

BERI-BERI. 

This  form  of  infectious  neuritis  is  often  associated  with  severe  or 
even  pernicious  anemia  (Spencer),  but  in  the  cases  which  reach  America 
the  anemia  is  usually  moderate  and  of  the  chlorotic  type.  In  three 
recently  imported  cases  of  the  disease,  each  with  moderate  fever  (100- 
101.5°  F.),  the  red  cells  ranged  between  3  and  3^  millions,  and  were 
very  deficient  in  Hb,  while  showing  no  other  changes,  except  for  the 
presence  of  microcytes.  Leucocytosis  was  absent  and  the  eosins  were 
not  increased.  Cabot  records  an  afebrile  case  with  3.9  million  red 
cells,  48  percent  Hb,  and  7,800  leucocytes. 

Daubler  found  normal  numbers  of  red  and  white  cells,  but  increase 
of  fat,  in  the  blood  of  three  cases. 

Numerous  attempts  to  demonstrate  the  infectious  agent  in  beri-beri 
are  thus  far  negative.  Various  bacteria  have  been  demonstrated  in 
the  blood  post-mortem.  The  latest  contribution  is  that  of  Fajardo 
who  believes  that  he  has  seen  in  the  red  cells  of  59  cases  a  protozoan 
resembling  the  parasite  of  Texas  fever  but  smaller  and  more  difficult 
to  stain. 

CHOREA. 

The  coincidence  of  St.  Vitus  dance  and  chlorosis  was  such  a  fre- 
quent clinical  picture  that  the  older  writers  regarded  the  anemia  as 
one  of  the  essential  causes  of  such  nervous  manifestations.  Although 
this  view  has  been  proven  untenable  it  remains  true  that  anemia  and 
chorea  have  many  common  antecedents,  that  the  blood  in  chorea 
usually  shows  a  slight  impoverishment,  and  that  anemia  is  a  very  fre- 
quent predisposing  cause  of  chorea. 

Burr  found  moderate  chlorotic  anemia  in  all  of  36  cases,  but  any 
severe  grade  was  always  referable  to  complications.  Leroux  found  5 
million  cells  in  2  cases,  between  3.4  and  4.8  millions  in  5,  and  2.2  mil- 
lions red,  89,000  white  in  an  infant  in  which  the  disease  was  compli- 
cated by  furunculosis.  Zappert's  four  cases  showed  moderate  reduction 
in  red  cells,  3.9-4.5  millions.  Litten  has  recorded  two  fatal  cases 
arising  in  the  course  of  pernicious  anemia.  Cabot  refers  to  12  cases 
showing  no  abnormality  except  eosinophilia. 

The  leucocytes  in  uncomplicated  cases,  have  been  found  normal  in 
numbers  but  often  with  excess  of  eosins.  Zappert  counted  630-1360 
(8-19  percent)  of  eosins  in  4  cases. 

The  bacteriological  examination  of  the  blood  during  life  has  thus  far 
been  negative,  although  Leredde  obtained  the  Staphylococcus  albus  from 
the  blood  of  one  case  complicated  by  endocarditis.  The  blood  of  the 
cadaver  has  been  found  to  contain  various  micro-organisms,  Triboulet 
having  3  positive  results  in  15  cases. 

Functional  nervous  diseases,  such  as  hysteria,  neurasthenia, 
hypochondriasis,  and  tetany,  do  not  give  rise  to  anemia,  but  numer- 
ous associated  conditions  may  lead  to  impoverishment  of  the  blood. 
Cabot  and  Reinert  report  mild  grades  of  chlorotic  anemia  in  hysteria 
and  neurasthenia.     In  neuritis  Cabot  reports  chlorotic  anemia  with 


336  NERVOUS  AND  MENTAL  DISEASES. 

marked  leucocytosis  (16,000-28,000)  in  a  febrile  case  in  a  young  sub- 
ject, while  in  4  of  6  cases  of  afebrile  alcoholic  neuritis  the  leucocytes 
were  slightly  increased. 

GRAVES'   DISEASE. 

Anemia  does  not  appear  to  be  essentially  connected  with  exophthal- 
mic goitre,  as  some  cases  show  nearly  normal  cells  and  Hb.  (Oppen- 
heimer.)  Bramwell  reports  anemia,  grade  not  stated,  in  only  27  of  64 
cases.  Yet  many  patients  suffer  from  a  form  of  anemia  closely  re- 
sembling chlorosis,  which  is  sometimes  quite  severe.  Thus  Zappert 
records  two  cases  with  2.8  and  2.7  million  cells,  and  32-30  percent  of 
Hb.  The  writer  has  examined  the  blood  in  several  such  cases,  in  one 
of  which  the  majority  of  red  cells  were  distinctly  undersized. 

The  term  "  thyroid  chlorosis  "  is  applied  by  Capitan  to  cases  of  chlo- 
rosis associated  with  enlargement  of  the  thyroid.  Referring  to  Hayem's 
report  of  29  goitres  among  35  chlorotic  patients,  Capitan  finds  reason 
to  believe  that  one  type  of  chlorosis  is  referable  to  thyroid  intoxication. 
Some  years  ago  the  writer  was  struck  by  the  peculiar  clinical  type  of 
chlorotic  anemia  observed  in  two  elderly  women  suffering  from  Graves' 
disease,  but  has  not  since  encountered  such  cases. 

The  leucocytes,  in  the  absence  of  complications,  are  normal  or  di- 
minished.    Neusser  and  Cabot  have  noted  relative  lymphocytosis. 

Bibliography. 

Nervous  and  Mental  Diseases. 

Burr.     Cited  by  Cabot. 

Capitan.     Compt.  Rend.  Soc.  Biol.,  1897,  p.  1073. 

Capps.     Amer.  Jour.  Med.  Sci.,  Vol.  Ill,  p.  650. 

Daubler.     Archiv  f.  Tropenhvg.,  1897,  p.  372. 

Fajardo.     Cent.  f.  Bact.,  Bd."24,  p.  558. 

Howard.     Bull.  N.  Y.  State  Hosp.,  I.,  1896,  p.  139. 

Jellife.     Bull.  N.  Y.  State  Hosp.,  1897,  p.  397. 

Kuhlmann.     Bull.  N.  Y.  State  Hosp.,  1897,  p.  77. 

Langdon,  Bamford.     Bull.  N.  Y.  State  Hosp.,  1896,  p.  239. 

Leredde.     Rev.  Mens.  Mai.  de  I'Enfanee,  1891. 

Leroux.     Mai.  de  I'Enfanee  (Grancher),  IV.,  p.  819. 

Lewis.     Text-book  of  Mental  Diseases,  1889,  p.  287. 

Litten.     Charit^-Annalen,  1884,  p.  265. 

McPhail.     Jour,  of  Mental  Sci.,  Vol.  30,  pp.  378,  488. 

Oppenheimer.     Deut.  med.  Woeh.,  1889,  p.  882. 

Pease.     Bull.  N.  Y.  State  Hosp.,  1896,  p.  133. 

Roncorini.     Archiv  di  Psychiat.,  1894,  p.  293. 

Seppili.     Ref.  in  Jour.  Mental  Sci.,  Vol.  34,  p.  143. 

Smyth.     Jour,  of  Insanity,  1890,  p.  505. 

Somers.     Bull.  N.  Y.  State  Hosp. ,  1896,  p.  75. 

Spencer.     Lancet,  1897,  I.,  p.  32. 

Steele.     Amer.  Jour,  of  Insanity,  Vol.  49,  p.  604. 

Sutherland.     Jour,  of  Mental  Sci.,  Vol.  31,  p.  147.  • 

Triboulet.     These  de  Paris,  1893,  cited  by  Leroux. 

Winckler.     Diss.  Bonn,  1891. 


PART  V. 
GENERAL  DISEASES  OF  VISCERA. 

CHAPTER    XX. 
THE   HEMOPOIETIC  SYSTEM. 

THE   LIVER. 

Relation  of  Its  Functions  to  the  Blood. — Although  the  chief  func- 
tions of  the  liver  in  the  secretion  of  bile  and  the  elaboration  of  ab- 
sorbed food  products  are  directly  concerned  with  the  maintenance  of 
the  blood  albumens,  specific  effects  of  inhibition  of  these  functions  have 
not  yet  been  traced  in  the  blood.  These  effects  are  doubtless  seen 
in  the  anemia  of  advanced  cirrhosis  but  are  even  then  not  to  be  dis- 
tinguished from  similar  changes  in  other  secondary  anemias. 

The  function  of  transforming  into  bilirubin  and  removing  from  the 
system  the  pigment  of  disintegrated  red  cells  is  being  constantly  ex- 
erted in  health  and  disease.  When  from  any  cause  the  excretion  of 
this  product  is  obstructed,  as  in  acute  yellow  atrophy,  or  the  demands 
upon  the  function  are  excessive,  as  in  pernicious  malaria,  either  hemo- 
globin, or  its  derivative  bilirubin,  accumulate  in  the  blood  giving  hem- 
oglobinemia  or  jaundice.  In  the  former  case  the  content  of  the  liver 
in  hematoidin  and  hemisiderin  is  an  accurate  index  of  the  grade  of 
blood  destruction.  There  is  as  yet  no  proof  that  the  liver  plays  more 
than  a  passive  part  in  the  destruction  of  blood. 

The  embryonal  function  of  the  liver  as  a  depot  of  forming  red  cells 
is  not  infrequently  retained  till  after  birth,  and  there  is  reason  to  be- 
lieve that  the  renewal  of  this  function  may  sometimes  give  peculiar 
character  to  the  anemia  of  infants  described  by  v.  Jaksch. 

Effects  of  Bile  upon  the  Blood. — A  globulicidal  action  of  bile 
■was  first  demonstrated  experimentally  by  Hunefeld  (1840),  while  the 
fact  that  the  biliary  acids  are  the  active  agents  in  dissolving  red  cells 
in  jaundice  was  show^n  by  v.  Dusch  (1854),  and  fully  established  by 
many  later  studies,  v.  Dusch  not  only  demonstrated  the  power  of 
bile  to  dissolve  red  cells,  but  claimed  that  it  may  also  dissolve  leuco- 
cytes and  even  liver  cells,  a  property  noted  also  by  Rywosch.  The 
relative  globulicidal  power  of  the  various  salts  of  biliary  acids  was 
ully  tested  by  Rywosch,  who  found  that  sodium  chenocholate  and 
taurocholate  dissolve  red  cells  when  in  a  concentration  of  1-700,  or 
1-600,  that  Na-cholate  is  only  moderately  active  at  1-200,  while  Na- 
22 


338  THE  HEMOPOIETIC  SYSTEM. 

glycocholate  destroys  red  cells  only  when  in  a  solution  of  1-50.  In 
the  process  of  solution  the  red  cells  first  lose  their  central  depression, 
become  variously  deformed  and  finally  dissolved,  leaving  no  detritus. 
These  changes  have  been  observed  only  in  the  test-tube,  but  in  the 
blood  of  most  cases  of  jaundice  the  process  appears  to  differ  from  that 
of  other  forms  of  hematocytolysis. 

The  resistance  of  the  red  cells  was  found  by  Limbeck,  in  all  cases  of 
jaundice,  to  be  distinctly  increased,  the  cells  not  dissolving  in  solutions 
of  more  than  .32  percent  NaCl  (normal  .46  percent).  This  change  he 
referred  to  the  destruction  of  less  resistant  cells  and  a  chemical  union 
of  Hb  and  stroma  brought  about  by  the  action  of  bile  salts. 

An  increase  in  specific  gravity  of  the  blood  was  observed  by 
Grawitz,  following  the  injection  of  bile  in  animals,  and  referred  by  him 
to  transudations  excited  by  some  specific  action  on  the  part  of  the 
bile.  Limbeck  also  found  a  relative  decrease  in  volume  of  the  serum 
in  obstructive  jaundice,  as  well  as  a  lower  percentage  of  chlorides.  At 
the  same  time  the  volume  of  the  red  cells  was  increased. 

Coagulation  is  hastened,  according  to  Rywosch,  by  the  presence  of 
one  part  of  Na-chenocholate  or  taurocholate  in  500  of  blood,  but 
entirely  inhibited  when  the  proportion  reaches  1-250. 

The  presence  of  bile  pigments  has  no  deleterious  action  on  the 
blood,  although  Rywosch  found  that  injections  of  pure  bilirubin,  while 
not  affecting  the  blood,  produce  mild  general  toxic  symptoms. 

Diseases  of  the  Liver. 

Jaundice. — In  the  human  subject  clinical  observations  have  shown 
that  small  traces  of  bile  are  demonstrable  by  the  greenish-yellow 
color  of  the  serum  of  very  mild  cases  in  which,  however,  there  are 
usually  no  other  changes  in  the  blood.  In  severe  cases,  when  con- 
siderable quantities  of  bile  are  present  in  the  circulation,  many  of  the 
effects  observed  in  the  experimental  study  of  jaundice  become  appar- 
ent. Any  tendency  toward  concentration  which  the  presence  of  bile 
may  exert  is  seldom  seen  clinically,  as  the  majority  of  severe  cases  of 
jaundice  exhibit  some  reduction  of  red  cells.  This  anemia  is  usually 
referable  to  preexisting  conditions,  but  in  very  severe  cases  actual 
destruction  of  red  cells  may  be  traced  in  the  dried  specimen.  A 
tendency  to  very  rapid  crenation,  and  total  absence  of  rouleaux, 
have  been  observed  by  Grawitz.  In  the  blood  of  icteric  infants 
Hofmeier  also  noted  deficiency  in  the  formation  of  rouleaux,  which, 
however,  are  normally  less  numerous  than  in  the  blood  of  adults. 

Evidences  of  solution  of  red  cells  were  found  by  Silberman'  in 
the  blood  of  many  jaundiced  infants.  These  consisted  in  the  presence 
in  the  blood  of  fragments  of  red  cells,  and,  in  the  liver  and  spleen,  of 
many  phagocytes  inclosing  red  cells  and  blood  pigment.  Many  other 
degenerative  changes  in  the  red  cells  were  noted  but  they  were  not 
necessarily  connected  with  the  jaundice.  In  severe  cases  examined  by 
the  writer,  besides  the  ordinary  signs  of  anemia,  there  were  in  the 


CANCER   OF  LIVER.  339 

blood  many  very  pale  and  some  fragmented  red  cells,  and  in  the 
viscera  deposits  of  pigment  equal  to  those  of  pernicious  malaria.  After 
death  reddish  acicular  crystals  (bilirubin  ?)  were  sometimes  found  in 
the  blood. 

A  POLYCYTHEMIA  referable  to  the  concentratino-  effect  of  bile  in  the 
blood  has  not  often  been  reported.  Yet  Becquerel  and  Rodier  reported 
the  highest  figures  in  their  experience  as  occurring  in  a  case  of  jaun- 
dice, and  later  observers  have  abundantly  shown  that  well-marked 
jaundice  markedly  increases  the  specific  gravity  of  the  blood,  in  pro- 
portion to  the  intensity  of  the  jaundice.  Grawitz  saw  the  gravity  rise 
from  1.050  to  1.061  in  a  severe  case,  but  does  not  report  the  number 
of  red  cells,  while  Limbeck  and  v.  Noorden  ^  found  the  dry  residue  of 
the  blood  to  be  22-25  percent  in  several  cases.  The  gravity  of  the 
serum  was  unaffected  by  the  presence  of  bile  in  Hammarschlag's  1 2 
cases,  but  in  Limbeck's  2  cases  the  serum  was  poor  in  chlorides.  The 
results  of  Limbeck's  chemical  analyses  indicate  that  the  volume  of  red 
cells  in  jaundice  is  much  increased. 

The  ALKALINITY  of  the  blood  is  in  mild  cases  unchanged  (Limbeck), 
but  in  acute  yellow  atrophy,  de  Renzi,  using  Reale's  method,  found  a 
neutral  reaction,  while  an  acid  reaction  was  present  in  severe  catarrhal 
jaundice  and  in  suppurative  hepatitis  with  jaundice. 

The  leucocytes,  in  simple  catarrhal  jaundice,  have  usually  been  found 
imaifected,  but  in  Grawitz'  experience  an  increase  has  been  common 
and  occasionally  the  leucocytosis  has  been  very  marked  (38,000-40,- 
000).  It  is  probable  that  different  observers  refer  to  different  types 
of  cases. 

Cancer  of  Liver. — A  large  proportion  of  the  carcinomata  of  the 
liver  being  primary  in  the  stomach,  the  anemia  of  this  condition  is  fre- 
quently grafted  upon  that  of  gastric  cancer.  The  reports  of  Wlajew 
include  one  case  of  secondary  pernicious  anemia  with  only  850,000 
red  cells,  and  none  showing  over  3  millions,  while  the  leucocytes  ran  be- 
tween 20,000  and  40,000,  indicating  that  this  anemia  is  usually  severe. 
The  writei''s  experience  at  autopsies  in  these  cases  accords  in  general 
with  Wlajew's  results,  as  marked  emaciation  and  distinct  oligemia  are 
usually  prominent.  The  sudden  onset  of  severe  jaundice  in  many  of 
the  cases  suggests  the  probability  that  the  blood  may  at  times  suffer 
concentration. 

Cabot's  series  of  17  cases  showed  well-marked  anemia,  cells  under 
3  millions  in  only  two,  while  in  10  there  were  over  4  millions. 

The  LEUCOCYTES  are  usually  increased  in  cancer  of  tlie  liver  but 
the  increase  is  often  intermittent.  Of  19  cases  Cabot  found  only  6 
with  white  cells  under  10,000,  and  in  none  of  these  six  was  the  ex- 
amination repeated.  Alexander  found  leucocytosis  in  two  cases,  but 
only  after  repeated  examinations.  The  grade  of  leucocytosis  is  usually 
moderate.  The  fact  that  when  attacking  the  liver  most  carcinomata 
are  already  generalizing,  the  tendency  toward  rapid  growth  in  the 
organ,  and  the  early  formation  of  further  metastases,  are  some  of  the 
factors  which  account  for  the  frequency  of  leucocytosis  in  hepatic  cancer. 


340  THE  HEMOPOIETIC  SYSTEM. 

Hypertrophic  Cirrhosis  with  Jaundice. — More  severe  alterations 
of  the  blood  have  been  observed  by  Hayem  in  a  case  of  hypertrophic 
cirrhosis  in  which  the  red  cells  fell  below  2  millions,  with  increased  Hb 
index  and  leucocytosis.  Severe  anemia  was  also  present  in  two  cases 
verified  at  autopsy  and  reported  by  Cabot,  but  in  one,  only  2,400  leu- 
cocytes were  found. 

Hanot  and  Meunier  have  insisted  upon  the  presence  of  leucocytosis 
in  this  form  of  cirrhosis  of  liver,  finding  therein  evidence  of  the  infec- 
tious nature  of  the  disease.  They  found  from  9,000-21,800  leucocytes 
in  5  cases.  Lukachewitch  also  found  20,000  white  cells  in  another 
case,  and  Auche  reports  in  three  cases  intermittent  leucocytosis,  12,400 
to  18,600  cells.  Bacteria,  usually  Staphi/lococciis  pyogenes  aureus,  have 
been  found  in  the  blood  of  "  infectious  jaundice,"  sometimes  with  hy- 
pertrophic cirrhosis,  by  Netter. 

Cholelithiasis. — Considerable  interest  attaches  to  the  bacteriological 
examination  of  the  blood  in  cholelithiasis  from  the  recent  discovery  of 
bacteria  in  the  blood,  in  several  cases,  usually  in  those  marked  by 
intermittent  fever.  Staphylococcus  j^yogenes  aureus  has  been  isolated 
in  two  cases  by  Netter,  in  three  cases,  once  with  the  colon  bacillus,  by 
Sittmann,  and  in  the  pus  of  metastatic  abscesses  by  Gilbert  and  Girode, 
Brieger,  and  many  others.  The  pneumococcus  of  Franhel  and  Strepto- 
coccus pyogenes  were  obtained  from  the  blood  in  one  case  each,  both 
complicated  by  hepatic  abscess,  by  Canon  and  by  Zancarol,  while  a 
small  bacillus,  not  identified,  was  obtained  from  a  complicating  hepatic 
abscess  and  from  the  ulcerated  heart  valves,  by  Netter  and  Martha. 

The  anemia  in  these  cases  varies  with  the  previous  condition  of  the 
patient  and  with  a  great  variety  of  associated  lesions. 

The  behavior  of  the  leucocytes  is  of  interest,  and  may  be  of  value  in 
differential  diagnosis.  Biliary  colic  may  supervene  in  severe  attacks 
without  producing  any  leucocytosis.  The  onset  of  jaundice  is  some- 
times accompanied  by  moderate  leucocytosis,  at  other  times  fails  to 
cause  any  increase  of  white  cells.  The  difference  probably  depends 
upon  the  grade  of  inflammation  excited  by  the  gall  stones,  etc.  Here 
as  elsewhere  one  may  expect  no  leucocytosis  with  simple  catarrhal  in- 
flammations but  with  active  suppurative  lesions  leucocytosis  may  reach 
a  pronounced  degree  (up  to  50,000,  Cabot).  As  some  of  these  lesions 
run  into  abscess  of  the  liver,  or  pyemia,  even  this  high  figure  is  prob- 
ably not  the  limit  of  the  leucocytosis. 

Abscess  of  Liver. — The  lesion  in  abscess  of  the  liver  may  follow 
one  of  several  types. 

1.  There  may  be  a  large  number  of  small  or  miliary  abscesses 
throughout  the  liver,  filled  with  creamy  or  muco-pus.  These  abscesses 
arise  from  extension  of  suppurative  cholangitis.  The  leucocytosis  is 
probably  a  continuation  of  that  observed  in  cholangitis,  but  there  ap- 
pear to  be  no  direct  observations  on  the  blood  of  this  condition. 

2.  There  may  be  one  or  two  large  cavities  filled  with  creamy  pus  or 
stringy  muco-pus,  and  well  shut  off  from  the  liver  tissue  by  mucous  or 
pyogenic  membrane.     The  writer  has  seen  such  an  abscess  run    its 


I 

I 


CIRRHOSIS  OF  LIVER.  341 

course  with  little  or  no  increase  of  white  cells  in  the  blood,  and  the 
leucocytosis  is  usually  slight.  In  one  adult  case,  the  day  before  J 
liter  of  muco-pus  was  evacuated  at  operation,  with  temperature  101° 
F.,  the  blood  showed  11,000  leucocytes,  52  percent  of  which  were 
mononuclear,  48  percent  polynuclear.  A  previous  examination  had 
also  failed  to  show  distinct  leucocytosis. 

3.  Large  necrotic  abscesses  with  actively-  suppurating  walls  are 
practically  always  attended  with  marked  leucocytosis,  up  to  50,000, 
but  this  increase  may  be  distinctly  intermittent. 

Acute  Yellow  Atrophy. — Cases  recorded  by  Grawitz  and  Cabot 
showed  5.15  million,  and  5.52  million  red  cells,  and  12,000-16,000 
leucocytes.  The  exact  limits  of  this  disease  are  as  yet  imperfectly  de- 
termined, but  in  three  cases  seen  by  the  writer  there  was  in  each  a 
moderate  leucocytosis,  15,000-21,000.  Two  of  these  occurred  in  par- 
turient women  at  Sloane  Maternity  Hospital  and  showed  the  usual 
lesions  in  the  liver.  In  another,  at  Roosevelt  Hospital,  the  disease 
lasted  three  weeks,  and  the  inner  four-fifths  of  the  hepatic  lobules  were 
necrotic.  The  red  cells  were  not  counted,  and  the  absence  of  rouleaux 
and  the  early  crenation  mentioned  by  Grawitz  were  not  noted.  In  two 
cases  bacteriological  examinations  of  the  blood  during  life,  by  Sitt- 
mann,  were  negative,  but  Vincent  obtained  the  colon  bacillus  from  the 
blood  of  one  case  during  life. 

Echinococcus  Cyst  of  Liver. — Hayem  classes  the  echinococcus 
cyst  of  the  liver  as  one  of  the  conditions  leading  to  leucocytosis  and 
excess  of  fibrin  in  the  blood.  Neusser  refers  to  an  increase  of  eosins 
in  the  same  condition.  Auche  in  one  case  ruled  out  the  diagnosis  of 
hypertrophic  cirrhosis  from  the  absence  of  an  excess  of  leucocytes,  the 
patient  showing  an  echinococcus  cyst  at  autopsy,  while  Wlajew  found 
no  change  in  the  blood  in  a  case  of  hydatid  cyst  of  the  liver. 

Cirrhosis  of  Liver. — In  the  early  stages  of  the  disease,  when 
digestion  is  not  much  impaired  and  there  are  neither  jaundice  nor  hem- 
orrhages, the  blood  is  but  little  altered.  Almost  invariably  the  Hb  is 
deficient.  During  the  progress  of  the  disease  the  blood  steadily  de- 
teriorates, giving  some  of  the  most  typical  examples  of  secondary 
anemia.  Abundant  cause  of  the  anemia  is  found  in  all  cases  in  the 
disturbance  of  the  functions  of  the  liver  and  stomach,  and  in  other 
cases  by  the  complications  of  the  particular  type  which  the  disease 
follows.  In  slowly  progressing  cases  without  special  complications, 
the  blood  commonly  shows  between  3-4  million  cells,  55—75  percent 
of  Hb,  and  little  or  no  leucocytosis. 

The  ordinary  progress  of  the  anemia  is  perhaps  most  affected  by 
PROFUSE  HEMORRHAGES,  after  which  the  blood  shows  the  usual  reduc- 
tion of  red  cells  and  Hb,  with  nucleated  red  cells  and  leucocytosis. 
Single  hemorrhages  may  occur  in  subjects  which  are  only  slightly 
anemic,  and  the  blood  is  then  rapidly  restored.  In  the  later  stages  of 
the  disease,  single  or  repeated  hemorrhages  if  not  at  once  fatal,  often 
ead  to  very  grave  secondary  pernicious  anemia. 

Ascites,  although  draining  the  blood  of  much  albumen,  is  com- 


342  THE  HEMOPOIETIC  SYSTEM. 

monly  found  with  lesser  grades  of  chlorotic  anemia.  It  is  not  un- 
common to  find,  in  well  advanced  cases  requiring  paracentesis,  4|  to  5 
million  red  cells  and  Hb  above  65  percent.  Grawitz  believes  that  the 
ascitic  transudate  leads  to  some  concentration  of  the  blood  and  the 
masking  of  anemia.  Such  a  condition  is  strongly  suggested  at  times 
by  the  disproportion  between  the  anemic  appearance  of  the  patient  and 
the  slight  changes  demonstrable  in  the  blood.  The  effects  of  tap- 
ping vary.  Limbeck  observed  a  case  of  Laennec's  cirrhosis,  with  ex- 
treme ascites,  in  which  the  removal  of  18  liters  of  fluid  raised  the  red 
cells  after  24  hours  from  3.28  millions  to  5.16  millions.  Three  days 
later  they  fell  to  3.54  millions.  Osterspey  noted  the  same  result  after 
several  tappings  of  the  same  patient.  On  the  other  hand  Grawitz  saw 
the  red  cells  fall  from  4.7  to  4.3  millions  shortly  after  tapping,  but 
the  first  examination  came  three  days  before  the  operation.  The  eifects 
of  tapping  may  very  well  vary  with  the  immediate  effects  upon  the 
circulation,  with  the  state  of  the  kidneys,  and  with  the  reappearance 
of  the  ascites. 

Jaundice,  if  mild,  has  no  demonstrable  influence  on  the  blood  of 
cirrhosis ;  nor  do  the  ordinary  chronic  forms  of  moderately  severe 
jaundice  appear  to  be  accompanied  by  any  special  alteration  in  the 
blood  except  a  tendency  toward  leucocytosis. 

In  most  of  the  jaundiced  cases  reported  by  Hayem,  Cabot,  and  others, 
there  was  a  moderate  leucocytosis,  reaching  20,000  or  more.  Severe 
jaundice  usually  occurs  in  advanced  and  anemic  cases,  or  in  the  hyper- 
trophic forms.  The  ordinary  cirrhotic  process  in  the  liver  is  unaccom- 
panied by  leucocytosis,  which  however  may  frequently  arise  from  many 
complications  or  accidental  causes.  Thus  Hayem,  Osterspey,  Cabot, 
and  others  found  no  leucocytosis  except  from  complications,  but  Gra- 
witz, Rosenstein,  and  Wlajew  refer  to  cases  with  moderate  leucocytosis, 
without  giving  details. 

DISEASES   OF   GASTROINTESTINAL   TRACT. 

Esophagus. — Stenosis  of  the  esophagus,  when  extreme,  by  diminish- 
ing the  quantity  of  fluids  ingested,  has  been  shown  to  lead  to  marked 
concentration  of  the  blood.  V.  Noorden  ^  refers  to  two  cases  of  can- 
cer of  esophagus  in  which  the  dry  residue  of  the  blood  reached  26.5  and 
27.3  percent  (normal  21-22  percent).  When  to  this  condition  of  con- 
centration are  added  the  cachexia  which  belongs  to  carcinoma  and  to 
starvation,  a  marked  degree  of  oligemia  may  result,  approaching  that 
of  pernicious  anemia.  A  distinctly  reduced  quantity  of  blood  was 
noted  at  autopsy  in  one  of  two  cases  of  epithelioma  of  esophagus, 
observed  by  the  writer  at  Roosevelt  Hospital,  while  in  the  other,  in 
which  death  resulted  from  pulmonary  extension  and  pneumonia,  the 
stenosis  was  not  extreme.  These  same  factors  may  perhaps  be  re- 
sponsible for  some  relative  increase  in  the  numbers  of  red  cells  which 
has  been  observed  in  a  few  cases.  The  red  cells  in  reported  cases 
have  been  above  normal,  or  very  slightly  reduced,  as  in  other  forms 


DISEASES  OF  THE  STOMACH.  343 

of  cancer,  or  greatly  reduced,  as  in  the  severe  anemia  of  cancerous 
cachexia. 

Comparing  his  own  results  in  a  single  case  with  those  of  Escherich, 
Pee,  and  Osterspey,  Rieder  concluded  that  the  cachexia  of  epithelioma 
of  the  esophagus  differs  from  that  of  carcinoma  in  other  regions  in 
the  absence  of  leucocytosis.  Reinbach  also  reported  two  cases  with 
relative  lymphocytosis.  Cabot  and  Hoffman,  however,  report  several 
cases  with  moderate  leucocytosis.  In  the  writer's  cases  there  was 
ante-mortem  increase  of  white  cells.  There  has  been  no  attempt  to  refer 
these  varying  results  to  the  special  causes  of  leucocytosis  to  which 
they  are  probably  due. 

Diseases  of  Stomach. 

General  Considerations. — Since  the  blood  depends  for  its  supply  of 
albumens  chiefly  upon  the  functional  activity  of  the  stomach,  there  is 
an  intimate  relation  between  the  condition  of  the  blood  and  the  ac- 
tivity of  digestion  and  absorption  in  this  organ. 

1.  Transitory  functional  disturbances  of  the  stomach  usually  fail 
to  notably  alter  the  blood,  but  persistent  vomiting  with  hyperacidity 
has  resulted  in  distinct  concentration  of  the  blood  and  reduction  of 
chlorides  both  in  blood  and  urine. 

2.  While  total  withdrawal  of  food  for  a  short  period  causes  com- 
paratively little  change  in  the  blood,  a  long-continued  failure  of  diges- 
tion or  absorption  is  one  of  the  most  efficient  causes  of  anemia.  It 
has  already  been  shown  that  organic  lesions  of  the  stomach  are  promi- 
nent among  the  pathological  findings  in  cases  of  pernicious  anemia, 
including  chronic  gastritis,  atrophy  of  gastric  mucosa,  stenosis  of  the 
pylorus,  and  cancer.  All  the  lesser  grades  and  types  of  anemia  are  ob- 
served, with  even  greater  frequency,  to  be  associated  with  gastric  lesions, 
while  the  anemia  of  marasmic  infants  is  doubtless  largely  owing  to  fail- 
ure of  digestion  and  absorption,  without  organic  lesion  in  the  stomach. 
Meynert's  theory  of  chlorosis  further  illustrates  the  well-founded  be- 
lief in  the  importance  of  normal  digestion  in  maintaining  the  condi- 
tion of  the  blood. 

3.  The  stomach  is  a  frequent  site  of  loss  of  blood  by  hemorrhage. 
If,  as  is  indicated  by  the  studies  of  Quincke,  and  of  Dettwyler  and  Sil- 
berman,^  anemia  or  hemoglobinemia  are  strong  predisposing  causes  of 
ulceration  of  the  stomach  and  duodenum,  there  is  in  the  interaction  of 
these  two  conditions  a  "  circulus  vitiosus  "  which  readily  explains  their 
frequent  association  in  the  same  subject,  and  the  very  severe  grades  of 
anemia  which  thereby  result.  Smaller  and  more  frequent  bleedings  also 
greatly  aggravate  the  anemia  which  accompanies  ulcerating  carcinoma. 

4.  Much  has  been  written  about  the  effects  of  gastro-intestinal 
toxemia,  but  the  chief  source  of  autotoxic  agents  is  without  doubt  the 
intestine. 

Special  Diseases. 

Acute  Gastritis,  Dyspepsia,  Hyperacidity. — These  conditions,  if 
not  prolonged,  have  no  tendency  to  produce  anemia.     If  vomiting  is 


344  THE  HEMOPOIETIC  SYSTEM. 

excessive  the  cells  and  Hb  may  be  increased.  The  leucocytes  are 
sometimes  increased,  sometimes  normal  or  diminished.  Their  numbers 
may  indicate  the  intensity,  but  not  the  etiology  of  the  inflammation. 

Chronic  Gastritis. — Chronic  gastritis  may  be  tolerated  for  long 
periods  without  leading  to  any  marked  anemia,  as  the  writer  has  often 
observed  in  private  cases  addicted  to  alcohol.  When  the  patients  be- 
come disabled,  anemia,  of  the  secondary  chlorotic  type,  is  usually  found 
to  be  associated  with  loss  of  flesh.  The  leucocytes  are  low,  and  lym- 
phocytes usually  prevail.  (Blindeman,  Cabot,  Hofiman.)  Digestion 
leucocytosis  may  be  diminished  and  is  sometimes  absent,  as  in  cancer. 

Associated  with  chronic  gastritis  and  fibrous  stricture  of  the  pylorus, 
the  Avriter  has  twice  observed  slowly  progressive  anemia  lasting  four 
and  five  years.  The  changes  in  the  blood  were  first  chlorotic,  later 
intermediate,  and  finally  those  of  pernicious  anemia,  without  many 
megaloblasts  in  the  blood,  but  with  typical  changes  in  the  marrow. 
Much  more  acute  and  typical  cases  of  pernicious  anemia  have  been  re- 
ferred to  chronic  gastritis.     (Pepper,  Stengel.) 

Dilatation  of  Stomach. — In  cases  of  gastrectasis  from  chronic  gas- 
tritis or  stenosis  of  pylorus  the  blood  does  not  differ  from  that  of 
simple  uncomplicated  chronic  gastritis.  Although  the  patients  become 
cachectic  and  lose  flesh,  the  blood  usually  fails  to  show  corresponding 
anemia.  In  the  cases  reported  by  Reinert,  Cabot,  Blindeman,  and 
others,  the  red  cells  and  Hb  were  normal  or  increased  or  but  slightly 
reduced.  It  is  generally  agreed  that  oligemia  exists  in  these  cases, 
but  its  origin  is  not  clear,  and  it  is  by  no  means  evident  that  the  con- 
centration of  the  blood  is  affected,  as  Kussmaul  suggests,  by  excessive 
vomiting.     Defective  absorption  is  j)robal)ly  a  more  important  factor. 

The  Blood  in  Gastro-intestinal  Diseases  of  Infants. — Acute  gas- 
tro-enteritis  occurring  in  healthy  infants  usually  tends  to  concentrate 
the  blood,  but  these  effects  are  demonstrable  only  in  severe  cases.  Fel- 
senthal  and  Bernhard,  in  20  cases,  found  uniform  polycythemia  reach- 
ing 7.5  million  cells,  and  usually  moderate  leucocytosis.  Hock  and 
Schlesinger  found  a  moderate  increase  in  specific  gravity  in  very  se- 
vere but  not  in  ordinary  cases.  On  the  other  hand  in  an  anemic 
rachitic  infant  with  diarrhea  the  Hb  fell  in  one  week  from  80  to  60 
percent,  indicating  that  a  preexisting  anemia  may  be  aggravated  by 
such  attacks. 

The  leucocytes  are  usually  increased,  Fischer  finding  a  well-marked 
lymphocytosis  with  60  percent  of  lymphocytes,  while  Hock  and 
Schlesinger  in  the  above-mentioned  case  found  38,000  leucocytes  the 
majority  of  which  were  large  lymphocytes.  In  hoo  cases  of  cholera 
infantum,  reported  by  Weiss,  the  lymphocytosis  approached  the  grade  of 
lymphatic  leukemia. 

In  chronic  gastro-enteritis  there  may  be  progressive  anemia  and 
emaciation,  as  in  Hayem's  case  in  which  after  2  months  the  red  cells 
numbered  only  685,000,  leucocytes  18,910.  On  the  other  hand, 
Monti  and  Berggrun  (p.  17)  report  a  case  lasting  6  weeks  in  which  the 
blood  of  the  emaciated  subject  showed  4.1  million  red   cells  and  65 


ULCER   OF  STOMACH.  345 

percent  of  Hb.  In  most  of  Felsentbal's  cases  the  Hb  rose  above  65 
percent,  only  when  there  was  marked  polycythemia,  while  moderate 
leucocytosis  was  the  rule. 

The  grade  of  anemia  observed  in  marasmio  wfants  with  mild  gastro- 
intestinal disturbance  is  very  variable,  and  its  different  phases  illus- 
trate all  the  stages  of  secondary  anemia.  It  is  usually  characterized 
by  relative  or  absolute  lymphocytosis. 

Ulcer  of  Stomach. — The  state  of  the  blood  in  ulcer  of  the  stomach 
is  extremely  variable  and  it  is  not  always  evident  what  conclusions  to 
draw  from  the  results  of  its  examination.  From  the  very  numerous 
cases  reported  in  greater  or  less  detail  by  Leichtenstern,  Laache, 
Haeberlin,  Oppenheimer,  F.  Muller,  Schneider,  Reinert,  Osterspey, 
Cabot,  Rochemont,  and  others,  as  well  as  from  the  writer's  own  obser- 
vation, these  changes  seem  to  fall  in  some  rather  distinct  classes. 

1.  Some  cases  appear  to  have  suffered  no  permanent  change  in  the 
composition  of  the  blood,  but  from  their  anemic  appearance  it  is  prob- 
able that  the  total  volume  of  blood  has  been  reduced,  without  marked 
alteration  in  its  quality. 

Most  of  these  patients  have  never  sustained  a  large  hemorrhage,  or  a 
former  loss  of  blood  has  been  replaced  through  the  active  regeneration 
which  is  often  seen  in  this  condition.  Muller  and  Oppenheimer  have  re- 
ferred especially  to  such  cases,  while  Grawitz  demonstrated  in  one  patient 
that  the  blood  was  decidedly  hydremic,  the  dry  residue  of  the  serum  being 
only  8.56  percent,  while  that  of  the  whole  blood  was  19.75  percent,  and  the 
red  cells  numbered  4.34  millions.  This  patient  was  recovering  from  more 
severe  anemia  and  still  gave  anemic  heart  murmurs.  A  single  chemical 
analysis,  while  most  important,  cannot  with  certainty  be  applied  to  all  these 
patients,  however,  and  several  of  Oppenheimer' s  reports  indicate  that  the 
blood  may  be  entirely  normal  in  some  cases  of  gastric  ulcer.  It  does  not 
seem  probable  that  vomiting  or  other  causes  of  concentration  of  the  blood 
are  important  factors  in  the  majority  of  these  cases. 

2.  The  usual  state  of  the  blood  is  one  of  marked  secondary  chlorotic 
anemia,  with  little  or  no  leucocytosis,  the  presence  of  which  depends 
largely  upon  the  manner  of  feeding.  While  the  regeneration  of  the 
blood  after  hemorrhage  is  often  very  rapid,  it  is  seldom  complete  while 
the  patient  remains  in  the  hospital,  and  there  seems  to  be  some  influ- 
ence, possibly  found  in  a  diminished  digestive  power  in  the  stomach, 
which  causes  the  anemia  to  persist. 

The  writer  followed  one  male  patient  for  5  years  after  a  dangerous  hem- 
orrhage, but  although  all  local  and  other  general  symptoms  had  disap- 
peared, the  blood  never  showed  more  than  75  percent  of  Hb. 

3.  The  bleedings  of  ulcer  of  the  stomach  furnish  some  of  the  most 
remarkable  examples  of  post-hemorrhagic  anemia,  the  characters  of 
which  have  been  described.  Surviving  patients  seldom  show  less  than 
one  million  cells,  but  from  this  point  may  improve  rapidly,  with  low 
Hb-index,  normoblasts,  and  leucocytosis.  '  Cases  with  cells  under  3 
millions  have  usually  suffered  from  hemorrhages,  which  if  frequently 
repeated  may  lead  to  grave  anemia  with  rising  Hb-index  and  increas- 
ing diameters  of  red  cells. 


346  THE  HEMOPOIETIC  SYSTEM. 

Leucocytes. — Leucocytosis  of  moderate  grade  follows  hemorrhage,  or 
local  inflammation.  In  one  case  with  marked  leucocytosis  the  writer 
found  two  perforated  ulcers,  one  opening  into  a  large  cavity  in  the 
liver,  the  other  connected  with  an  abscess  of  the  liver.  In  quiescent 
periods,  with  rectal  feeding,  there  is  usually  hypoleucocytosis,  while 
the  change  to  feeding  by  the  stomach  may  excite  considerable  diges- 
tion leucocytosis,  as  in  Cabot's  case,  in  which  the  first  meal  raised  the 
white  cells  from  4,000  to  15,000.  These  features  may  be  of  diagnos- 
tic value  when  cancer  is  suspected,  but  should  be  interpreted  with  cau- 
tion. Digestion  leucocytosis  has  been  absent  in  10  cases  of  ulcer  re- 
ported by  Hoffman,  Hassmann,  and  Schneyer.  In  three  of  these  there 
was  stenosis  of  pylorus. 

Cancer  of  Stomach. — The  usual  course  of  the  anemia  of  malignant 
neoplasms  is  varied  by  the  peculiar  conditions  connected  with  a  tumor 
of  this  organ,  and  by  the  extent  and  character  of  the  new  growth. 
In  the  reports  of  some  200  cases  to  be  found  in  the  literature  there 
has  been  no  systematic  attempt  to  classify  the  types  of  anemia  with 
reference  to  the  character  of  the  tumor,  and  while  it  appears  by  no 
means  certain  that  such  a  classification  would  be  of  clinical  value, 
there  are,  nevertheless,  certain  features  of  the  growth  and  complica- 
tions of  these  tumors  which  chiefly  determine  the  state  of  the  blood. 

1.  8ome  cancers  of  the  stomach  exist  for  considerable  periods  without 
leading  to  marked  impoverishment  of  the  blood,  and  there  is  no  necessary 
<5ause  of  anemia  in  the  early  stages  of  most  of  those  which  do  not 
bleed,  ulcerate,  or  contract  the  pylorus.  When  chronic  gastritis  or 
ulcer  precede  cancer,  the  preexisting  anemia  suffers  at  the  time  no 
appreciable  change.  Accordingly,  it  is  a  common  experience  to  find 
in  the  blood  at  this  time  no  distinct  indication  of  the  presence  of  a  ma- 
lignant tumor  in  the  body.  At  this  time  the  general  symptoms  are 
more  reliable  diagnostic  signs  than  is  the  state  of  the  blood.  Moreover, 
if  vomiting  is  a  prominent  early  symptom,  an  initial  anemia  may  be 
masked  by  temporary  concentration  of  the  blood.  Thus  Cabot  re- 
ports over  4  million  red  cells  in  34,  and  over  5  millions  in  19,  out  of 
'72  cases. 

The  first  sign  of  affection  of  the  blood  is  seen  in  the  falling  Hb  which 
has  been  found  considerably  reduced  in  many  of  the  cases  with  normal 
or  nearly  normal  red  cells. 

2.  In  the  majority  of  case^  of  gastric  cancer  the  red  cells  are  reduced 
in  number,  the  Hb  is  deficient,  and  the  blood  shoios  the  changes  of  second- 
ary chlorotic  anemia.  The  reduction  of  cells  is  sometimes  remarkably 
slight,  but  the  Hb  usually  suffers  first  and  most  severely.  When  dis- 
tinct cachexia  is  present,  both  red  cells  and  Hb  are  nearly  always  re- 
duced, unless  there  is  active  vomiting.  Poikilocytosis  appears  in  the 
more  chronic  and  severe  cases.  Nucleated  red  cells  are  usually  seen 
in  small  numbers.  Sometimes  they  are  present  when  the  anemia  is 
very  slight.  Jez  found  them  so  common  in  cancer  and  so  rare  in  ulcer 
as  to  furnish  diagnostic  evidence  between  these  conditions. 

The  Hb-index  is  commonly  subnormal  but  not  so  low  as  in  chloro- 


CANCER   OF  STOMACH.  347 

sis.  Osier  and  McCrae,  however,  found  an  index  of  .63  in  52  cases, 
which  is  nearly  as  low  as  that  of  chlorosis.  The  Hb  is  very  much 
less  likely  to  increase  when  once  low,  while  it  does  increase,  frequently 
and  rapidly,  in  simple  ulcer.     (Blindeman.) 

The  conditions  which  tend  to  develop  severe  anemia  in  gastric  can- 
cer are  chiefly  hemorrhage,  ulceration,  and  metastasis.  Diffuse  growths 
and  annular  pyloric  tumors  have  less  effect  upon  the  blood. 

3.  A  moderate  2yroportion  of  cancers  of  the  stomach  pursue  a  course 
which  clearly  resembles  that  of  jiernicious  anemia.  Without  very  marked 
gastric  symptoms  and  with  no  demonstrable  tumor,  the  blood  becomes 
excessively  anemic,  the  red  cells  falling  to  a  low  figure,  usually  about 
1^-1  millions,  megalocytes  are  abundant,  and  nucleated  red  cells,  some 
of  which  may  be  of  large  size,  make  their  appearance. 

The  type  of  carcinoma  €ound  in  tliese  cases  varies.  Sometimes  there  is 
a  small  tumor  of  the  stomach  wall  with  moderate  neighboring  metastasis, 
suggesting  the  development  of  cancer  in  an  old  round  ulcer.  Sailer  and 
Sadler  report  such  cases,  and  the  writer  has  seen  two  others  at  autopsy. 
Usually  the  tumor  is  of  considerable  size  and  ulcerating,  as  in  another  case 
reported  by  the  writer.  It  is  not  probable,  however,  that  the  grave  form  of 
anemia  is  necessarily  associated  with  any  particular  forms  of  cancer,  as  both 
the  above  types  may  be  seen  without  extreme  anemia. 

In  the  diagnosis  of  this  type  of  gastric  cancer  from  pernicious 
anemia,  one  is  usually  aided  in  the  examination  of  the  blood  by  the 
following  features  : 

(a)  The  majority  of  megalocytes  do  not  show  an  excess  of  Hb,  which 
is  distinctly  more  deficient  than  in  pernicious  anemia. 

(6)  Megaloblasts  are  rare,  and  nucleated  red  cells,  if  present,  are 
mostly  of  normal  size  or  but  slightly  larger  than  normal. 

(c)  There  is  usually  polynuclear  leucocytosis  in  advanced  carcinoma 
of  stomach. 

The  leucocytosis  may  fail  and  a  few  megaloblasts  may  be  present, 
but  the  writer  has  been  unable  to  find  a  case  of  grave  anemia  in  cancer 
of  the  stomach  in  which  the  general  deficiency  of  Hb  was  not  marked. 

Henry  calls  attention  to  the  fact  that  in  cancer  the  cachexia  exceeds 
the  oligocythemia,  while  in  pernicious  anemia  the  opposite  relation 
holds,  but  the  anemic  type  of  gastric  cancer  has  in  several  reported 
cases  reduced  the  red  cells  below  IJ  millions,  the  limit  noted  in  his 
experience.  In  his  statement  that  at  death  pernicious  anemia  leaves 
fewer  red  cells  (usually  below  1  million)  than  gastric  cancer  (usually 
above  1  million)  most  observers  will  concur. 

Leucocytosis  in  G-astric  Cancer. — Polynuclear  leucocytosis  is  present 
in  the  majority  of  cases  but  not  in  all.  In  the  early  stages  of  the  dis- 
ease, when  diagnoses  are  difficult,  leucocytosis  is  frequently  absent,  and 
if  we  exclude  the  slight  increases,  the  majority  of  early  cases  fail  to 
show  leucocytosis.  This  fact  probably  depends  on  the  usual  absence 
of  any  cause  of  leucocytosis,  which  the  tumor  itself  does  not  furnish. 
Without  much  regard  to  the  position  of  the  tumor  or  the  rapidity  of 
growth,  leucocytosis  makes  its  appearance  as  a  result  of  ulceration, 


348  THE  HEMOPOIETIC  SYSTEM. 

exudative  inflammation  about  the  tumor,  hemorrhage,  metastasis,  and 
anemia.  In  the  writer's  experience  these  causes  are  most  active  in  the 
order  named.  A  single  examination  of  the  blood  is,  however,  quite 
insufficient  to  exclude  the  occurrence  of  the  leucocytosis  which  is  now 
under  consideration.  The  leucocytosis  of  secondary  anemia  is  often 
intermittent,  according  to  the  process  which  it  follows,  and  its  detection 
may  require  repeated  examinations. 

The  grade  of  leucocytosis  is  usually  not  high,  but  since  in  low  states 
of  nutrition  the  leucocytes  are  usually  low,  the  presence  of  10,000 
leucocytes  has  here  more  significance  than  in  states  of  health.  The 
majority  of  advanced  cases  show  between  10,000  and  20,000  white 
cells.  Extreme  leucocytosis  has  usually  been  found  to  result  from 
complicating  inflammation,  extensive  ulceration,  or  numerous  meta- 
stases. It  is  said  that  some  cases  may  pursue  their  course  entirely 
without  leucocytosis. 

When  the  total  numbers  are  distinctly  increased  the  proportion  of 
polynuclear  leucocytes  is  usually  high.  This  fact  is  specially  apparent 
in  the  cases  reported  by  Osier  and  McCrae.  Eosinophile  cells,  how- 
ever, are  nearly  always  present,  and  sometimes  their  numbers  and  pro- 
portions are  considerably  increased  (5-6  percent).  It  is  of  interest  to 
note  that  Labbe  has  found  many  eosinophile  cells  in  the  tissue  in  and 
about  an  excised  cancer  of  the  stomach,  as  well  as  in  the  adjoining 
lymph  nodes. 

Digestion  Leucocytosis  in  Cancer  of  Stomach. — R.  Muller,  in  1890, 
first  called  attention  to  absence  of  digestion  leucocytosis  in  cancer  of  the 
stomach,  and  this  fact  has  since  been  abundantly  verified  by  the  reports 
of  Schneyer,  Hoffman,  Hartung,  Capps,  Sailer,  Cabot,  Hassman,  and 
Jez 

Muller,  Schneyer,  Jez,  and  Hartung  found  no  digestion  leucocytosis  in 
their  41  cases,  while  in  simple  ulcer  it  was  always  present,  except  in  one  case 
of  hematemesis.  Hartung  found  it  present  in  four  cases  of  cancer  of  other 
organs.  Capps  and  Cabot  report  digestion  leucocytosis  of  3,270-3,850  cells, 
in  3  of  37  cases,  while  it  was  present  in  only  5  of  10  cases  of  chronic  gastritis 
and  in  one  case  of  fibrous  stricture  of  pylorus.  More  recently  Hoffman ,  finding 
digestion  leucocytosis  in  3  of  24  cases  of  cancer,  but  in  only  2  of  9  cases  of 
ulcer  of  stomach,  and  in  only  2  of  11  cases  of  anacidity  from  other  causes, 
denies  any  great  diagnostic  value  in  the  test.  Hassman  and  Schneyer  also 
found  no  digestion  leucocytosis  in  three  cases  of  ulcer  with  pyloric  stenosis, 
while  Sailer  found  no  digestion  leucocytosis  in  one  case  of  tuberculous  ca- 
chexia, and  in  two  cases  Avith  preexisting  inflammatory  leucocytosis.  Osier 
and  McCrae  demonstrated  an  increase  of  33  percent  of  leucocytes  following 
digestion  in  10  of  22  cases  of  gastric  cancer. 

The  above  studies  showing  that  digestion  leucocytosis  is  absent  when 
the  stomach  fails  either  to  digest  or  absorb  with  considerable  activity, 
conditions  which  usually  but  not  necessarily  accompany  carcinoma  but 
which  may  also  be  found  in  simple  ulcer,  chronic  gastritis,  stenosis  of 
pylorus,  gastroptosis,  anacidity,  tuberculosis,  etc.,  it  appears  that  this 
test  can  hold  only  a  very  subordinate  position  in  the  diagnosis  of  can- 
cer of  the  stomach. 


DISEASES  OF  THE  INTESTINE.  349 

Duodenal  Ulcer  closely  resembles  gastric  ulcer  in  its  effects  upon 
the  blood. 

Diseases  of  the  Intestine. 

The  blood  is  very  closely  dependent  upon  the  absorptive  and  ex- 
cretory functions  of  the  intestine  both  for  its  transient  variations  in  con- 
centration and  its  more  permanent  supply  of  albumens.  So  marked 
and  prompt  is  the  response  of  the  blood  to  these  changing  conditions, 
that  no  examination  of  the  blood  requiring  accurate  calculation  should 
be  made  without  full  regard  to  the  condition  of  the  gastro-intestinal 
tract.  The  writer  has  repeatedly  seen  an  attack  of  typhoid  fever  com- 
pletely obliterate  the  signs  of  a  moderate  chlorosis  ;  and  has  previously 
referred  to  the  remarkable  transformation  of  the  blood  observed  when, 
at  Montauk  in  1898,  typhoid  fever  developed  in  subjects  of  malarial 
cachexia.  Of  the  two  main  intestinal  functions  the  blood  responds 
much  more  promptly  to  excessive  excretion  than  to  increased  absorption. 

Effects  of  Absorption. — During  the  early  stages  of  digestion  of 
solid  food  the  red  cells  tend  to  increase,  owing  to  the  discharge  of  a 
considerable  bulk  of  digestive  fluids.  (Buntzen,  Sorenson,  Leichten- 
stern.)  With  largely  fluid  diet,  on  the  other  hand,  the  absorption  of 
fluids  may  tend  from  the  first  to  diminish  the  red  cells,  so  that  their 
lowest  proportion  is  found  about  four  hours  after  meals.  At  the  same 
time  coagulation  is  slower.  (Vierordt,  Leichtenstern.)  The  increased 
flow  of  lymph  doubtless  contributes  to  this  result.  With  proper  diet 
in  healthy  adults,  these  processes  usually  fail  to  cause  important  vari- 
ations in  the  red  cells  and  Hb  of  the  blood,  and  even  when  the  quan- 
tity of  fluid  in  the  food  is  excessive  or  extremely  deficient,  the  demonstra- 
ble effects  are  slight  and  very  transient.  Leichtenstern  could  detect 
no  change  in  a  patient  who  drank  21.5  liters  of  water  during  three 
days,  and  Schmaltz  found  only  a  slight  reduction  in  gravity  (1.059  to 
1.057)  forty-five  minutes  after  the  ingestion  of  4  liters  of  physiological 
salt  solution.  The  ingestion  of  very  large  quantities  of  fluid  can  dilute 
the  blood  only  to  a  slight  degree,  beyond  which  the  activity  of  the 
kidneys  is  sufficient  to  carry  off  all  excess  and  keep  the  gravity  of  the 
blood  within  somewhat  narrow  limits. 

Depletion  of  the  blood  by  limited  ingestion  of  fluids  and  especially 
by  watery  exudates  leads,  on  the  other  hand,  to  very  prompt  and  consider- 
able concentration  of  the  blood.  Numerous  clinical  illustrations  of  this 
fact  have  already  been  considered  as  arising  from  disorders  of  the 
stomach,  but  the  more  extreme  examples  are  connected  with  the  use  of 
purges  and  with  diseases  of  the  intestine,  especially  those  attended 
with  active  diarrhea. 

Effect  of  Purges  Upon  the  Blood. — It  was  held  by  Poisseuil  in 
1839  that  when  salines  are  administered  in  greater  concentration  than 
that  of  the  blood  serum,  the  laws  of  osmosis  determine  the  passage  of 
fluids  from  the  blood  into  the  intestine.  It  has  since  been  shown  that 
with  many  laxatives  other  factors  lead  to  the  same  result,  especially 
he  increased  intestinal  secretion  and  the  failure  of  absorption. 


350  THE  HEMOPOIETIC  SYSTEM. 

Brouardel  first  demonstrated  an  increase  of  blood  cells  following  purga- 
tion finding  that  with  severe  diarrhea  the  red  cells  might  rise  as  much  as 
1  456  000  per  cmm.  The  leucocytes  were  at  the  same  time  increased, 
maximum  5,880,  but  apparently  for  different  reasons  and  not  in  proportion 
to  the  red  cells.  Later,  Hay  found  an  increase  of  nearly  2  million  red  cells 
within  1\  hours  after  the  administration  of  a  large  dose  of  Glauber's  salt. 
The  increase  began  in  a  few  minutes,  and  the  normal  condition  was  restored 
in  about  4  hours.  The  effects  were  more  marked  the  more  concentrated 
the  solution  ;  but  after  a  certain  concentration  of  blood  had  been  reached,  no 
further  effects  could  be  induced  and  no  purgation  followed  the  continued  ad- 
ministration of  the  saline.  Likewise  Grawitz  found  the  administration  of  15 
grains  of  Epsom  salt  in  50  cc.  water  to  raise  the  gravity  of  the  blood,  be- 
ginning in  5  minutes  and  reaching  a  maximum  increase,  from  1.0591  to 
1.0539  in  42  minutes,  after  which  there  was  a  steady  decline.  Common  salt 
was  even  more  active  ;  15  grains  in  a  little  water  on  an  empty  stomach  rais- 
ing the  gravity  of  the  blood  from  1,050  to  1.060  within  20  minutes.  The  ef- 
fects of  such  salines  he  found  were  largely  nullified  when  the  stomach  and 
intestines  contained  much  food. 

Colitis  (Dysentery). — Acute  colitis  of  croupous  or  ulcerative  type 
usually  causes  some  concentration  of  the  blood  and  is  attended  with 
considerable  leucocytosis.  After  the  acute  febrile  period,  if  the  patient 
survives,  anemia  replaces  the  oligemia  and  the  leucocytosis  becomes 
intermittent.  Yet  the  writer  has  seen  excessively  emaciated  cases  of 
acute  amebic  colitis  die,  without  fever,  and  without  marked  reduction 
in  the  proportion  of  red  cells. 

Chronic  ulcerative  colitis,  when  attended  by  much  purulent  exu- 
date and  numerous  hemorrhages  may  lead  to  extreme  anemia  of 
secondary  chlorotic  or  pernicious  type.  Leucocytosis  if  present  is 
intermittent. 

Catarrhal  colitis  has  little  effect  upon  the  blood,  tending  by  deple- 
tion to  raise  the  proportion  of  red  cells.  There  is  usually  no  leuco- 
cytosis. 

Simple  acute  diarrhea  causes  a  slight  and  transitory  increase  of  cells 
and  Hb. 

Cholera  morbus  and  the  severe  gastro-enteritis  of  infants  must  have 
a  pronounced  effect  in  concentrating  the  blood  and  masking  anemia,  but 
no  detailed  studies  in  this  field  are  apparently  at  hand. 

Cholera. — The  most  extreme  grades  of  concentration  of  the  blood 
are  seen  in  those  cases  of  Asiatic  cholera  w'hich  die  in  the  algid  stage, 
and  in  which  the  system  has  been  excessively  depleted  by  prolonged 
diarrhea.  The  diminution  in  the  quantity  of  blood  may  even  be 
plainly  visible  to  the  naked  eye,  in  the  scanty  hemorrhage  which  fol- 
lows section  of  an  artery.     (Dieffenbach.) 

The  principal  changes  in  the  blood  of  cholera  are  fully  set  forth  in 
the  first  systematic  study  of  the  subject  by  Schmidt,  who  in  specimens 
obtained  by  venesection  found  the  specific  gravity  of  the  whole  blood 
raised  from  1.050-1.059  to  1.065  or  1.073,  of  the  serum  from  1.029  to 
1.047.  Even  the  red  cells  were  found  to  suffer  a  marked  loss  of  water, 
their  gravity  rising  from  1.088  to  1.102.  Moreover,  while  the  in- 
crease in  density  of  the  blood  and  serum  was  not  uniform  nor  in  all 
cases  well  marked,  the  changes  in  the  red  cells  were  pronounced  and 


CHOLERA.  351 

invariable.  Schmidt's  analyses  were  not  made  in  the  most  extreme 
cases,  however,  and  the  relation  between  the  gravities  of  the  blood, 
the  cells,  and  the  serum,  indicate  that  the  relative  quantity  of  serum 
had  remained  about  normal.  Other  and  older  observers  (Thomson) 
had  previously  noted  a  gravity  of  the  serum  as  high  as  1.057,  indi- 
cating that  the  serum  had  begun  to  suffer  disproportionately  in  bulk, 
and  that  a  true  oligoplasmia  existed. 

Schmidt  and  Biernacki  added  to  the  knowledge  of  the  subject  the 
fact  that  all  chemical  constituents  are  increased  in  rather  uniform  pro- 
portion except  the  sodium  chloride,  which  seems  to  transude  in  the 
stools  in  excessive  quantity.  Biernacki,  finally,  has  shown  that  these 
excessive  grades  of  depletion  of  the  blood  do  not  exist  unless  the 
tissues  are  themselves  seriously  drained  of  fluids  and  can  no  longer 
supply  water  to  the  blood. 

The  coagulability  was  found  by  Hayem  and  Winter  to  be  sometimes 
normal,  but  often,  in  the  stage  of  reaction,  much  increased.  They 
found  a  much  diminished  capacity  of  the  blood  to  absorb  oxygen. 

The  alkalescence  of  the  blood  in  cholera  was  regarded  by  the  older 
observers  as  extremely  deficient,  and  Cantani  in  1884  claimed  to  have 
demonstrated  a  rapid  decrease  of  alkalinity,  a  neutral  reaction  during 
the  algid  stage,  and  even  an  acid  reaction  before  death.  This  change 
he  referred  to  excess  of  COg,  and  he  recommended  treatment  by  alka- 
lies. Biernacki  refers  the  diminished  alkalinity  to  loss  of  sodium. 
Hayem  and  Winter  examined  twelve  specimens  of  blood  during  the 
stage  of  collapse,  finding  four  of  them  neutral  or  slightly  alkaline, 
and  eight  slightly  acid.  The  reaction  has  not  been  determined  by 
more  recent  methods. 

The  red  cells  are  markedly  increased  in  nearly  all  cases.  In  one 
instance  they  rose  to  7.662  millions  within  24  hours,  the  patient  finally 
recovering.  Usually  the  red  cells  rise  to  6^-7J  millions,  and  this  ex- 
cess is  usually,  but  not  always,  proportionate  to  the  other  evidences  of 
concentration.  One  case  showed  a  maximum  of  over  8  million  red 
cells,  while  another  gave  only  3.193  millions  during  the  stage  of  reac- 
tion. Beginning  concentration  ha^  been  noted  as  early  as  the  third 
hour.  Biernacki  attributes  to  the  thickening  of  the  blood  and  espe- 
cially to  the  depletion  of  tissues  considerable  importance  in  the  patho- 
genesis of  symptoms  but  found  very  severe  symptoms  in  patients  not 
showing  much  diarrhea. 

Morphological  changes  in  the  red  cells  have  not  been  noted  by  most 
observers,  but  Nicati  reports  that  in  hemorrhagic  and  jaundiced  cases 
there  are  many  shadows  of  dissolving  red  cells,  and  often  pigmented 
leucocytes,  to  be  seen,  especially  in  the  stage  of  reaction. 

Leucocytosis  is  practically  constant  in  all  marked  cases.  Biernacki 
found  21,250  cells  in  one  mild  case  suffering  chiefly  from  diarrhea, 
but  only  4,375  in  another  very  similar  case.  Eight  cases  showing  in 
the  algid  stage  very  high  leucocytosis,  40,000-60,000,  were  fatal. 
Some  cases  with  more  moderate  leucocytosis  (20,000-30,000)  were 
also  fatal,  but  less  rapidly.     In  the  stage  of  reaction  the  leucocytes  are 


352  THE  HEMOPOIETIC  SYSTEM. 

usually  lower,  but  some  fatal  cases  show  a  persistent  or  increasing  leu- 
cocytosis  in  this  stage.  The  increase  of  leucocytes  is  relatively  much 
greater  than  that  of  the  red  cells.  It  has  been  noted  as  early  as  the 
twelfth  hour,  and  may  persist  as  long  as  6  days.  The  polynuclear 
cells  are  in  great  excess,  and  eosins  are  usually  absent. 

Bacteriology  of  tlie  Blood. — The  comma  bacillus  has  apparently  not 
been  found  in  the  blood  during  life.  After  death  it  was  recovered 
from  the  heart's  blood  in  a  small  proportion  of  48  cases  examined  by 
Lesage  and  Macaigne,  and  in  4  of  11  cases,  examined  8-24  hours 
after  death  by  Kekowsky.  Wlaew  failed  to  obtain  positive  results 
from  the  heart's  blood  in  several  cases,  and  one  specimen  of  blood 
drawn  during  life  was  sterile  and  non-pathogenic  to  animals.  Dia- 
troptoff  also  found  3  sterile  specimens  of  heart's  blood. 

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23 


CHAPTER    XXI. 
LUNGS,    HEART,   KIDNEYS. 

DISEASES    OF    THE    LUNGS. 

Respiratory  Changes  in  the  Blood. — During  its  passage  through 
the  lungs  the  blood  undergoes  certain  changes  which  in  their  normal 
progress  belong  to  the  physiology  of  the  blood,  but  when  disturbed  by 
pathological  conditions  may  considerably  aiFect  both  its  chemistry  and 
its  morphology. 

The  absorption  of  O^,  which  results  partly  by  simple  absorption  by 
the  plasma,  but  largely  by  chemical  union  with  Hb,  raises  the  volume 
of  this  gas  in  arterial  blood  to  21  percent  as  against  12  percent  for 
venous  blood,  while  the  discharge  of  COg  from  the  tissues  into  the 
plasma,  where  about  two-thirds  of  it  exist  as  a  bicarbonate  and  one- 
third  in  the  red  cells,  increases  the  CO2  content  of  venous  blood  to  46 
volume  percent  from  38  percent,  the  average  content  of  arterial  blood. 

The  character  of  the  diet  considerably  influences  the  ratio  of 
COg  excretion  to  O2  absorption,  which  with  carbohydrate  food  main- 
tains a  proportion  of  about  1  to  1,  while  with  highly  albuminous  diet 
more  oxygen  is  absorbed  and  devoted  to  oxidation,  and  the  ratio  is  .74 
to  1.     (Pembry.) 

Arterial  blood  was  long  supposed  to  be  richer  than  venous  in  solids 
and  Hb  (Kruger),  but  Cohnstein  and  Zuntz  showed  this  apparent 
thickening  to  be  due  to  stasis  caused  by  the  procedures  followed  in 
venesection  ;  and  with  Kruger  and  others  these  observers  demonstrated 
that  the  blood  in  larger  arteries  and  veins  is  equally  rich  in  red  cells, 
Hb,  and  dry  residue. 

An  important  diiference  between  venous  and  arterial  blood  was 
demonstrated  by  Hamburger,  who  showed  that  under  the  influence  of 
CO2  the  isotonic  tension  of  the  red  cells  is  moderately  increased,  so 
that  chlorides  and  water  pass  more  readily  from  plasma  into  cells, 
while  albumens,  alkalies,  and  probably  also  phosphoric  acid,  pass  from 
cells  to  plasma.  A  simultaneous  increase  of  the  sugar  and  fat  of  the 
serum  was  also  noted,  but  its  origin  not  fully  determined.  As  a  result 
of  these  alterations  in  osmotic  characters,  the  red  cells  of  venous  blood 
were  found  to  swell  and  assume  a  more  spheroidal  shape.  Limbeck, 
who  also  verified  this  change  in  the  osmotic  qualities  of  the  red  cells 
in  venous  blood,  referred  the  excess  of  dry  residue  of  the  plasma  not 
to  withdrawal  of  albumens  from  the  cells  but  to  absorption  of  the 
water  of  the  plasma  by  the  red  cells,  which  he  found  to  suffer  an  in- 
crease of  volume  in  venous  blood. 


DISEASES  OF  THE  LUNGS.  355 

With  the  increase  of  CO2  in  venous  blood  those  observers  who  iden- 
tify alkalinity  with  C02-content  found  an  increased  acid-neutralizing 
power  in  venous  blood.  This  anomalous  result,  viz.,  the  increase  of 
alkalinity  of  a  fluid  by  the  addition  of  an  acid,  they  referred  to  the 
withdrawal  of  alkaline  salts  from  the  tissues  for  the  neutralization  of 
the  acid. 

It  is  of  prime  importance  in  considering  the  pathogenesis  of  symp- 
toms in  various  anemias  to  call  attention  to  several  studies  which  have 
demonstrated  that  Hb  has  a  strong  chemical  affinity  for  oxygen  and 
that  this  attraction,  rather  than  the  percentage  of  O2  in  the  air,  chiefly 
regulates  the  supply  of  oxygen  to  the  tissues.  Lukjanow  first  showed 
that  by  increasing  the  pressure  of  the  O^  in  the  lungs  he  could  not  add 
to  the  quantity  of  absorbed  oxygen,  although  arterial  blood  is  not  sat- 
urated with  oxygen,  while  Lowy  found  that  neither  by  increasing  the 
pressure  to  1,400  mg.  Hg,  nor  by  lowering  it  to  40  mg.  (normal  760 
mg.),  could  the  blood  be  made  to  absorb  more  or  less  O2.  Beyond 
these  points  hovvever  the  absorption  of  O^  begins  to  vary.  Turning 
their  attention  to  the  respiratory  processes  in  anemia,  Kraus,  Chvostek, 
Bohland,  and  especially  Biernacki,  found  that  the  quantity  of  oxygen 
that  can  be  exhausted  from  blood  remains  about  the  same  although 
the  Hb  may  vary  greatly,  that  in  simple  anemia  the  system  instead  of 
using  less  oxygen  employs  rather  more  than  in  health,  and  only  in  the 
severest  forms  of  anemia  is  the  percentage  of  oxygen  in  the  blood  dis- 
tinctly reduced. 

It  therefore  appears,  as  Grawitz  concludes,  that  the  oxygenation  of  the 
blood  in  the  lungs  is  not  regulated  by  the  laws  of  diffusion,  and  is  not 
closely  dependent  upon  the  atmospheric  pressure  nor  upon  the  amount  of 
Hb  in  the  blood,  but  is  governed  by  a  special  chemical  activity  residing  in 
the  Hb. 

The  laws  governing  the  respiratory  changes  in  the  blood,  thus  briefly 
sketched,  principally  apply  to  chemical  processes,  but  have  important 
bearing  also  upon  certain  morphological  changes  seen  in  conditions  of 
dyspnea,  asphyxia,  and  in  the  peculiar  state  of  the  blood  observed  at 
high  altitudes. 

The  EXHALATION  OF  VAPOR  DURING  RESPIRATION,  while  not  fol- 
lowed under  normal  conditions  (Dastre)  by  any  concentration  of  the 
blood,  may,  if  we  accept  the  results  of  Grawitz's  observations  in  patho- 
logical states,  lead  to  considerable  loss  of  water  and  increase  of  red  cells 
and  dry  residue.  Grawitz  examined  the  blood  of  an  hysterical  woman 
before  and  after  a  prolonged  attack  of  hysterical  dyspnea,  in  which  the 
respirations  rose  to  100  per  minute,  and  found  the  red  cells  increased 
from  4.9  to  5.1 1  millions,  the  dry  residue  of  the  whole  blood  from  19.78 
percent  to  22.08  percent,  and  that  of  the  serum  from  9.54  percent  to 
9.85  percent.  A  similar  result  was  noted  after  he  had  voluntarily  in- 
creased his  own  respiration  to  40  per  minute  during  a  period  of  one 
and  three-fourth  hours. 

Asphyxia. — During  dyspnea  from  disease  of  heart  or  lungs  there  is 
proportionate  increase  of  COj  in  the  blood.     (Kraus,  Chvostek.)    In  ex- 


356  LUNGS,   HEART,   KIDNEYS. 

treme  asphyxia  Zuntz  collected  the  results  of  nineteen  analyses,  which 
gave  for  O.,  0.96  volume  percent  and  49.53  percent  of  COg.  In  the 
attempt  to"discharge  CO2  from  the  tissues  and  to  supply  O^,  respira- 
tion is  accelerated,  and  the  same  result  is  attained  by  the  polycythemia 
which  results  from  venous  stasis.  Among  the  results  following  the  ex- 
cess of  CO  in  the  blood  is  an  alteration  in  the  red  cells  which  renders 
the  Hb  more  readily  diffusible  in  the  plasma.  This  change,  while  not 
apparently  leading  to  hemoglobinemia  during  life,  is  evident  after  death 
in  the  reddish  tinge  of  the  serum.  One  of  the  prominent  signs  in  the 
blood  of  asphyxia  is  the  failure  of  coagulation,  which  is  often  very 
complete  and  is  probably  referable  to  the  presence  of  CO2.  Ottolenghi, 
examining  the  blood  of  asphyxiated  rabbits,  found  it  to  be  thinner  and 
more  diffusible,  while  the  red  cells  were  reduced  in  number,  resistance, 
and  specific  gravity.  In  the  peripheral  blood  of  the  human  subject, 
during  rapid  asphyxia,  there  are  all  the  evidences  of  extreme  concen- 
tration. In  the  slower  forms  of  asphyxia,  which  are  accompanied  by 
pallor,  the  blood  has  apparently  not  been  compared  with  that  of  the 
more  rapid  cases. 

Emphysema. — The  blood  in  emphysema  varies  considerably  accord- 
ing to  the  state  of  the  circulation  and  respiration. 

During  the  intervals  ivhen  the  circulation  is  at  its  best  and  cyanosis  is 
absent,  an  anemic  condition  may  be  demonstrated  in  many  cases,  which 
is  referable  to  the  malnutrition  of  the  patients  or  to  complications, 
especially  cirrhosis  of  liver,  nephritis,  and  chronic  gastritis.  When 
cyanosis  becomes  chronic  most  observers  have  found  more  or  less  poly- 
cythemia and  increase  in  specific  gravity  (Peiper,^  Grawitz^),  but  in 
Leichtenstern's  cases  this  concentration  was  apparently  insufficient  to 
obscure  the  anemia,  as  he  reported  a  loss  of  Hb  in  patients  suffering 
from  cyanosis,  edema,  and  heart  failure.  An  increase  in  the  volume 
of  red  cells  up  to  8  tj.  has  been  described  by  Vaquez,^  in  cases  of 
chronic  cyanosis  from  various  causes.  During  asthmatic  attacks  with 
cyanosis,  the  blood  becomes  still  further  concentrated  and  the  expressed 
drop  may  appear  almost  black. 

The  leucocytes  are  usually  of  high  normal  average,  but  during  the 
asthmatic  attacks  there  may  be  distinct  leucocytosis.  When  bronchitis 
is  added  the  leucocytes  may  be  markedly  increased.  With  or  with- 
out leucocytosis  a  considerable  proportion  of  the  leucocytes  may  be  of 
the  eosinophile  variety.  Gabritschewsky,  who  called  attention  to  this 
excess  of  eosins  in  the  blood  corresponding  to  their  increase  in  the 
sputum  of  many  asthmatic  patients^  found  in  3  cases  from  11  to  22 
percent  of  eosins,  while  Fisk  reported  14.6  percent  in  one  case,  and 
Billings  found  as  many  as  53.6  percent  out  of  8,300  cells.  From  the 
observations  of  Leyden,  v.  Noorden,  and  especially  of  Schwerschew- 
ski,  it  has  been  shown  that  excess  of  eosins  in  the  blood  of  asthmatics 
occurs  principally  or  only  at  the  time  of  the  paroxysm,  that  they  in- 
crease with  repeated  attacks,  diminish  shortly  after  the  paroxysm  and 
with  the  appearance  of  expectoration,  and  in  the  intervals  largely  dis- 
appear.    Since  there  is  no  such  tendency  to  eosinophilia  in  the  suffoca- 


DISEASES  OF  THE  HEART.  357 

tive  attacks  of  endocarditis,  nor  in  the  severe  dyspnea  of  Bright's  dis- 
ease, the  examination  of  the  blood  may  serve  to  distinguish  bronchial 
asthma  from  other  forms  of  dyspnea,  and  may  perhaps  indicate  the  ap- 
proach of  a  paroxysm.  Teichmuller  and  Fuchs,  however,  find  many 
eosinophile  cells  in  other  forms  of  bronchitis. 

Bronchitis. — Acute  catarrhal  bronchitis  of  ordinary  severity  and  af- 
fecting the  larger  bronchi  only,  has  little  effect  upon  the  red  cells  and 
seldom  raises  the  number  of  leucocytes.  In  some  severe  cases  the 
writer  has  found  as  many  as  15,000  white  cells,  when  the  patient's 
temperature  was  104°.  In  some  of  Cabot's  cases  the  leucocytosis  was 
slightly  higher. 

Capillary  bronchitis,  with  high  temperature  and  marked  prostration, 
may  strongly  resemble  lobar  pneumonia  in  clinical  features,  and  like 
pneumonia,  is  accompanied  by  marked  leucocytosis.  In  three  fatal 
cases  with  high  temperature,  dyspnea,  and  cyanosis,  the  writer  found 
18,000-37,000  leucocytes.  At  autopsy  there  were  signs  of  severe 
general  bronchitis,  no  consolidation,  but  well-marked  chronic  nephri- 
tis. In  two  cases  without  autopsy,  Cabot  found  as  high  as  41,000 
leucocytes. 

DISEASES    OF    THE    HEART. 

The  majority  of  observations  on  the  blood  of  chronic  endocarditis 
have  shown  more  or  less  continuous  polycythemia  and  concentration 
of  the  blood.  The  more  important  of  these  studies  have  been  con- 
tributed by  Nasse,  Naunyn,  Toenissen,  Bamberger,  Lichtheim,  and 
Reinert,^  who  have  referred  this  concentration  to  stasis  from  local 
vasomotor  or  general  cardiac  paresis,  to  transudation  of  serum,  or 
(Naunyn)  to  a  physiological  effort  on  Nature's  part  to  furnisli  more 
oxygen  by  increasing  the  cells  and  Hb  of  the  blood. 

The  opposite  condition,  of  hydremia,  has  been  found  more  usual  or 
regarded  as  more  important,  by  Leichtenstern,  Oertel,  Oppenheimer, 
Stintzing  and  Gumprecht,  and  many  others,  who  hold  that  an  excess 
of  lymph  from  various  sources  passes  into  the  vessels  as  a  result  of 
lowered  blood  pressure.  Schneider  and  Limbeck  find  that  while  mitral 
lesions  are  usually  associated  with  polycythemia,  aortic  insuffi^ciency  more 
often  leads  to  hydremia. 

All  observers  are  agreed  that  the  valvular  lesion  and  the  usual 
causes  leading  to  it  exert  little  or  no  effect  upon  the  blood,  and  while 
differing  as  to  their  significance  all  admit  that  the  changes  in  the  blood 
vary  considerably  at  different  periods  of  the  disease. 

The  conflicting  views  have  been  carefully  studied  and  partially  uni- 
fied by  Grawitz,  who  finds  that  the  blood  shows  three  different  states, 
according  to  the  stage  of  the  disease,  and  determined  chiefly  by  the  de- 
gree of  compensation  established  in  the  heart. 

1.  When  valvular  lesions  are  fully  compensated  by  cardiac  hyper- 
trophy, and  when  there  are  few  or  no  symptoms  of  disease  of  this  or 
other  organs,  the  state  of  the  blood  depends  entirely  on  the  constitu- 
tion and  state  of  nutrition  of  the  individual. 


358  LUNGS,    HEART,   KIDNEYS. 

2.  When  disturbances  of  compensation  begin,  when  the  heart  muscle 
fails,  and  the  pulse  is  accelerated,  and  dyspnea  and  its  train  of  symp- 
toms appear,  changes  occur  in  the  blood  which  are  clearly  referable 
to  the  diminished  force  of  the  heart. 

The  whole  blood  loses  in  specific  gravity  and  in  dry  residue,  while 
its  content  of  water  increases,  and  these  changes  are  more  marked  in 
the  veins  than  in  the  superficial  capillaries.  The  red  cells  are  reduced 
in  number  but  they  suiFer  no  changes  in  size  or  in  Hb-content.  The 
leucocytes  show  no  characteristic  changes.  The  blood  serum  shows  the 
most  marked  changes,  always  becoming  more  watery.  These  altera- 
tions Grawitz  refers  solely  to  the  lowered  blood  pressure,  which  is  fol- 
lowed by  dilatation  of  capillaries  and  passage  of  tissue  fluids  into  the 
blood  stream.  Oliguria  may  result  from  the  same  factors  but  is  not 
the  cause  of  the  hydremia. 

3.  When  chronic  venous  stasis  is  established  and  dyspnea,  cyanosis, 
and  edema  exist,  the  changes  in  the  blood  are  more  complicated. 

Under  these  circumstances  the  blood  loses  water,  becomes  richer  in 
red  cells,  and  more  so  in  the  capillaries  than  in  the  veins.  These  ef- 
fects Grawitz  believes  to  result  from  transudation  of  fluids  through  the 
capillaries  into  the  tissues,  but  increased  exhalation  from  the  congested 
lungs,  and  possibly  also  increased  evaporation  from  the  skin,  contrib- 
ute to  the  same  result.  When  the  balance  of  pressure  between  capil- 
laries and  tissues  has  been  adjusted,  any  added  failure  of  the  heart  may 
be  followed  by  still  lower  pressure  and  temporary  hydremia. 

Grawitz's  deductions  have  appeared  to  most  critics  to  be  only  partially 
valid.  In  the  first  stage  it  is  generally  agreed  that  the  blood  is  usually  nor- 
mal, and  it  is  also  fully  demonstrated  that  a  fall  of  blood  pressure  leads  to 
relative  hydremia,  but  his  explanation  of  the  origin  of  the  polycythemia 
of  chronic  endocarditis  has  not  proven  fully  satisfactory.  As  Limbeck 
points  out,  many  patients  always  show  some  reduction  of  red  cells  whether 
compensation  is  complete  or  not ;  while  others  show  considerable  variations 
in  red  cells  without  apparent  relation  to  the  action  of  the  heart,  or  the  pres- 
ence or  absence  of  edema,  or  the  activity  of  the  kidneys.  Limbeck,  there- 
fore, attributes  less  importance  to  the  interchange  of  fluids  between  the 
blood  and  tissues,  and  believes  that  the  polycythemia  of  heart  disease  is 
partly  referable  to  the  same  obscure  factors  which  increase  the  red  cells  in 
high  altitudes.  That  there  is  an  actual  new  formation  of  red  cells  in  the 
polycythemia  of  endocarditis  is  held  by  Marie,  Reinert,^  and  others. 

Without  entering  further  into  the  details  of  individual  opinions,  it 
appears  certain  from  the  studies  already  cited  and  from  others  contrib- 
uted by  Siegl,  Peiper,*  Schmaltz,  Banholzer,  Maxon,  Stintzing  and 
Gumprecht,  that : 

1.  In  advanced  endocarditis  with  failing  compensation,  there  is  a 
distinct  tendency  toward  concentration  of  the  blood,  which  at  times  in- 
creases the  red  cells  to  8  millions  or  more. 

2.  This  polycythemia  is  the  combined  result  of  venous  stasis,  dysp- 
nea and  cyanosis,  transudation  of  blood  serum,  and  possibly  also  of 
other  obscure  factors  which  lead  to  polycythemia  in  high  altitudes. 

3.  The  state  of  the   blood  in  chronic   endocarditis  responds   to  a 


I 


DISEASES   OF  THE  HEART.  359 

limited  extent,  but  not  invariably  to  diuretics,  diaphoretics,  purges,  and 
heart  tonics, 

4.  The  constant  tendency  toward  anemia  is  usually  masked  by  the 
peculiar  condition  of  the  circulation. 

5,  The  result  of  the  examination  of  the  blood  must  be  interpreted 
only  with  strict  regard  to  the  general  condition  of  the  patient. 

Results  of  Blood  Examinations  in  Chronic  Endocarditis. — The  forego- 
ing statements  are  fully  borne  out  by  a  review  of  the  reported  exami- 
nations of  the  blood  in  endocarditis.  In  some  series  of  cases  the 
polycythemia  is  very  uniform,  as  found  especially  by  Oppenheimer  and 
Reinert,  while  the  Hb  commonly  runs  from  90— 110  percent.  Usually 
the  red  cells  do  not  exceed  6  millions,  but  some  cases  with  cyanosis 
reach  7  or  even  8  millions.  On  the  other  hand  a  slight  reduction  of 
cells,  not  below  4  millions,  appears  in  most  cases  reported  by  other 
observers.  Maxon's  statement  that  the  blood  of  heart  disease  com- 
monly shows  slight  variations  above  or  below  the  normal  in  red  cells, 
specific  gravity,  and  albumens,  is  the  only  rule  of  general  application. 

That  aortic  insufficiency  is  usually  found  with  less  concentrated 
blood  is  also  apparent  in  nearly  all  comparative  studies.  (Schneider, 
Grawitz,  Limbeck,  Menicanti,  Reinert,  Hayem,  Sadler.)  Yet  even 
here  the  red  cells  seldom  fall  below  4  millions. 

Variations  from  the  above  rules  are  not  unknown,  as  some  cases 
with  cyanosis  have  shown  less  than  4  million  red  cells,  and  aortic  in- 
sufficiency may  lead  to  polycythemia.  Much  depends  upon  the  par- 
ticular circumstances  surrounding  each  patient,  which  must  always  be 
regarded  with  care. 

The  LEUCOCYTES  in  uncomplicated  cases  show  no  important  varia- 
tions from  the  normal,  but  with  concentrated  blood  they  are  apt  to  be 
rather  above  the  average  normal  figures.  During  the  febrile  periods 
which  mark  the  terminal  stages  of  many  cases,  leucocytosis  of  con- 
siderable grade  is  usual.  The  complications  of  endocarditis  which 
cause  leucocytosis  are  numerous,  and  ante-mortem  leucocytosis  is 
usually  prolonged  and  pronounced. 

Malignant  Endocarditis. — The  more  acute  cases  of  bacterial  endo- 
carditis furnish  some  of  the  most  typical  examples  of  septicemia,  in 
which  the  blood  shows  rapid  loss  of  cells,  albumens,  and  Hb,  leucocy- 
tosis, and  very  often  bacteria  in  demonstrable  numbers. 

The  anemia  of  malignant  endocarditis  is  of  rapid  progress  and 
usually  becomes  one  of  the  characteristic  features  of  the  disease.  Be- 
ginning in  patients  with  practically  normal  blood,  the  septic  process 
often  reduces  the  red  cells  within  two  to  three  weeks  to  3.5  or  3  mil- 
lions, or  even  lower.  In  some  cases,  usually  those  of  longer  duration, 
the  anemia  is  less  marked  (over  4  million  cells),  or  is  masked  by  the 
febrile  process  and  by  venous  stasis.  In  all  the  markedly  septic  cases, 
however,  the  anemia  becomes  severe.  In  the  later  stages  of  severe 
cases  the  evidences  of  destruction  of  red  cells  become  marked,  the  Hb 
is  very  deficient  and  may  become  dissolved  in  the  plasma,  shadow  cor- 
puscles appear  in  the  fresh  specimen,  and  various  forms  of  degeneration 


360  LUNGS,   HEART,   KIDNEYS. 

of  red  cells  are  demonstrable  in  the  dry  specimen.  In  such  cases  the 
red  cells  may  not  number  much  over  one  million.  After  death  the 
deposits  of  blood  pigment  in  the  viscera  are  very  abundant  and  closely 
simulate  those  of  pernicious  malaria,  for  which  they  may  readily  be 
mistaken. 

Leucocytosis  is  present  probably  in  all  cases,  but  is  often  inter- 
mittent and  single  observations  may  fail  to  discover  it.  In  this,  as  in 
other  forms  of  sepsis,  there  may  be  a  tendency  to  slight  leucocytosis 
with  high  proportion  of  polynuclear  cells,  and  in  general  the  increase 
of  white  cells  is  not  very  marked,  considering  the  condition  of  the 
patient.  Roscher  and  Cabot  report  fatal  cases  with  8,000  and  8,900 
leucocytes  shortly  before  death,  while  Krebs  found  ante-mortem  leuco- 
cytosis of  44,200,  and  Grawitz  reported  168,000. 

Baeteriological  examination  of  the  blood  is  often  required  in  the  di- 
agnosis of  obscure  cases.  From  the  rather  limited  number  of  recorded 
examinations  by  reliable  methods  it  appears  that  bacteria  are  always 
to  be  found  in  the  blood  in  a  certain  group  of  cases  of  ulcerative  endo- 
carditis. These  cases  include  the  examples  of  cryptogenic  infection 
which  run  an  acute  septic  course  and  end  fatally  within  a  few  weeks 
or  months.  In  the  cases  of  ulcerative  endocarditis  which  terminate 
with  septic  fever  and  in  which  an  acute  process  is  often  added  to  the 
chronic  lesion,  cultures  of  the  blood  are  usually  negative.  Grawitz' 
claim  that  repeated  negative  cultures  are  sufficient  to  rule  out  ulcerative 
endocarditis  cannot,  however,  be  admitted  ;  for  the  evidence  rather 
favors  Kuhnau's  view  that  the  difference  between  "  simple  "  ulcerative 
and  malignant  endocarditis  is  one  of  degree,  not  of  kind,  and  that  in 
many  cases  of  subacute  or  chronic  ulcerative  endocarditis  of  bacterial 
origin  the  blood  is  sterile. 

These  groups  of  cases  are  illustrated  by  the  reports  of  several  investiga 
tors.  Grawitz  2  examined  7  cases  of  suspected  ulcerative  endocarditis,  all 
of  which  gave  negative  cultures  but  only  one  of  which  proved  to  have  an 
ulcerative  lesion.  In  three  pronounced  cases  of  malignant  endocarditis  he 
obtained  in  two  Staphylococcus  pyogenes  aureus,  in  one  Diplococcus  lanceolatus. 
Kraus  examined  the  blood  in  7  cases,  finding  the  streptococcus  in  one,  negative 
cultures  in  six.  Petruschky,  examining  the  blood  from  a  wet  cup,  obtained 
the  Streptococcus  pyogenes  in  one,  and  a  negative  result  in  the  other,  of  two 
cases.  Kuhnau  had  only  one  positive  result  {Staphylococcus  pyogenes  aureus) 
in  12  cases  examined.  Cohn  in  2  acute  cases  found  in  one  both  Streptococ- 
cus pyogenes  smd  Staphylococcus  aureus,  and  in  the  other  Staphylococcus  aureus 
alone,  while  in  two  chronic  cases  the  cultures  were  negative.  James  and 
Tuttle  obtained  positive  cultures  in  3  of  4  fatal  cases,  once  finding  the  Dip- 
lococcus lanceolatus.  White  obtained  negative  results  in  two  cases  3-4  days 
before  death,  but  isolated  Staphylococcus  pyogenes  aureus  from  both  just  be- 
fore death.  The  writer,  using  5-10  cc.  of  blood  drawn  from  the  median 
basilic  vein,  obtained  pure  cultures  of  Streptococcus  pyogenes  in  two  typical 
cases  of  malignant  endocarditis.  These  patients  gave  no  history  of  cardiac 
disease  until  the  development  of  a  septic  febrile  process  which  continued 
without  intermission  for  1-6  months,  and  until  death.  In  four  cases  of 
chronic  ulcerative  endocarditis  ending  with  septic  fever  cultures  of  the  blood 
were  negative. 

Gonorrlieal  Endocarditis. — The  gonococcm  has  been  obtained  in  pure 


DISEASES  OF  THE  KIDNEY. 


361 


culture  from  the  circulating  blood  of  cases  of  endocarditis  by  Thayer 
and  Blumer,  and  Thayer  and  Lazear,  and  Halle.  In  all  cases  the 
blood  was  extremely  anemic,  red  cells  under  2  millions,  while  the 
leucocytosis  was  slight,  12,000-14,000  in  one  case,  and  8,500-18,000 
in  the  others.  Many  cases  of  gonorrheal  septicemia  collected  by 
these  authors  indicate  the  frequency  with  which  this  germ  is  probably 
connected  with  endocardial  lesions. 

Columbini,  also,  obtained  the  gonococcus  in  cultures  of  the  circulating 
blood  in  a  case  of  gonorrheal  septicemia  with  endocarditis,  and  dem- 
onstrated its  identity  and  pathogenic  qualities  in  the  human  urethra. 

McCallum  and  Hastings  report  a  case  of  acute  endocarditis  from 
which  they  obtained  from  the  circulating  blood  cultures  of  a  somewhat 
peculiar  coccus  resembling  Streptococcus  pyogenes. 

Significance  of  the  Bacteriological  Examination  of  the  Blood  in  Endo- 
carditis.— 1.  A  positive  result  when  obtained  under  proper  precautions, 
and  long  enough  before  death  to  avoid  ante-mortem  secondary  infec- 
tions, places  beyond  doubt  the  infectious  nature  of  the  process. 

2.  A  negative  result  does  not  indicate  that  the  vegetations  do  not 
contain  bacteria  in  their  substance  or  on  their  surface.  A  large  num- 
ber of  negative  bacteriological  examinations  of  the  blood  have  been 
recorded  in  cases  showing,  post-mortem^  various  bacteria  in  and  on  the 
inflamed  heart  valves. 

From  personal  experience  of  moderate  extent  the  writer  has  drawn  the 
impression  that  when  malignant  endocarditis  follows  the  type  of  pure  septi- 
cemia with  cardiac  symptoms  in  the  background,  bacteriological  examina- 
tion of  the  blood  is  usually  positive,  but  when  cardiac  symptoms  are  or  have 
been  prominent,  bacteriological  examination  of  the  blood  is  usually  negative. 

Congenital  Heart  Disease. — The  pronounced  cyanosis  from  which 
most  of  these  patients  suffer  leads  to  extreme  degrees  of  concentration 
of  the  blood,  as  the  following  cases  will  show : 


Author. 

Red  cells. 

Leucocytes. 

Hb. 

S.  G. 

Krehl 

8  mil. 

8.9 

9.44 

8.47 

6.70 

8.10 

8.82 

7.54 

8.43 

Vaquez^ 

Banholzer 

160% 

110 

92 

1.071 

Gibson 

12,000 
12,000 
16,000 

Carmichael 

Toenisson  , 

Cabot 

Townsend  has  recently  reported  13  cases  in  which  the   red  cells 
varied  between  5.6  and  11.8  millions. 


DISEASES    OF    THE    KIDNEY. 

The  existence  of  marked   hydremia  in  cases  of  nephritis  was  dem- 
onstrated in  several  earlier  studies   of  the  chemistry  of  the   blood 


362  LUNGS,   HEART,   KIDNEYS. 

(cited  by  Gorup-Besanez),  but  Schmidt's  analyses  first  clearly  showed 
the  more  exact  nature  of  this  hydremia. 

In  three  patients  with  albuminous  urine  and  marked  edema,  he  found 
considerable  loss  in  specific  gravity  of  the  whole  blood  (1.043-1.051),  and  of 
the  serum  (1.018-1.024),  while  the  red  cells  remained  nearly  normal  in 
gravity  (1.081-4)  but  were  much  reduced  in  bulk  (34.2  from  44.9  percent). 
These  changes  were  believed  to  result  largely  from  the  loss  of  albumens  of 
the  serum,  while  the  Hb  of  the  red  cells  and  the  salts  of  the  plasma  were 
but  slightly  affected.  Scherer's  analyses  in  six  cases  demonstrated  a  de- 
crease in  the  solids  of  the  whole  blood,  and  a  loss  of  5  percent  of  the  albu- 
mens, although  the  fibrin  was  sometimes  increased.  The  red  cells  were  re- 
duced but  their  dry  residue  relatively  increased.  Although  the  serum  was 
very  watery,  the  dry  residue  averaging  6.9  percent,  the  salts  of  the  serum 
were  increased.  Very  low  gravity  of  the  serum,  1.019-1.023,  was  also  noted 
by  Becquerel  and  Rodier. 

From  numerous  other  analyses  by  Frerichs,  Gorup-Besanez,  Hinter- 
berger,  and  others,  it  began  to  appear  that  the  composition  of  the  blood  varies 
considerably  in  different  stages  of  the  disease,  and  later  studies  have  shown 
that  the  two  main  clinical  and  pathological  types  of  the  disease,  the  chronic 
exudative  and  the  chronic  productive  without  exudation,  are  attended  with 
distinct  changes  in  the  blood. 

1.  Chronic  Exudative  (Parenchymatous)  Nephritis. — The  albu- 
minuria and  edema  of  this  group  of  cases  are  associated  with  well- 
marked  anemia,  which,  however,  is  subject  to  great  variations  on  ac- 
count of  the  intermittent  course  of  the  disease  and  of  the  frequent 
disturbing  effects  of  treatment. 

The  usual  condition  of  the  blood  is  one  of  moderate  chlorotic  anemia. 
The  majority  of  cases  show  between  3  and  5  million  red  cells  and  40- 
80  percent  of  Hb.  The  reported  series  of  cases  in  the  literature  show 
wide  variations  in  the  condition  of  the  blood.  Considerable  polycy- 
themia is  not  infrequently  encountered.  Leichtenstern  and  Sorensen 
found  little  reduction  of  Hb  and  an  average  of  4.74  million  red  cells, 
while  Laache  and  Reinert  ^  found  a  low  Hb-percentage  with  slight 
loss  of  cells.  These  changes  represent  the  condition  most  commonly 
found.  Cases  with  less  than  2  million  cells  are  reported  by  Grawitz, 
Sadler,  Cabot,  and  are  not  rare.  In  these  and  occasionally  in  other 
cases  the  writer  has  sometimes  found  a  high  or  increased  Hb-index, 
and  at  autopsies  in  cases  of  pernicious  anemia  has  several  times  found 
the  lesions  of  chronic  productive  nephritis  with  exudation. 

These  variations  are  well  illustrated  by  Cabot's  synopsis  of  35  cases 
from  the  Massachusetts  General  Hospital. 

Red  cells.  Cases. 

6  7  millions 3 

5-6        "  6 

4-5        "  12 

3-4        "  11 

2-3        "  2 

1-2        "  1 

The  attempt  to  analyze  the  causes  of  the  variations  of  the  anemia  in 
chronic  nephritis  is  met  with  difficulties,  and  numerous  factors  must  be 
considered.     Polycythemia  results  from  cyanosis,  disturbance  of  cir- 


DISEASES  OF  THE  KIDNEY.  363 

culation,  and  rapid  transudations,  and  each  of  these  conditions  may  and 
frequently  does  obscure  pronounced  anemia.  An  astonishing  degree 
of  pallor  of  the  face  may  thus  be  found  with  5  million  red  cells  and 
100  percent  of  Hb.  The  progressive  anemia  of  the  average  case  is 
clearly  referable  to  the  loss  of  albumens  of  the  serum  and  general 
malnutrition.  Yet  the  real  advance  of  the  anemia  is  often  disturbed 
by  the  intermittent  losses  of  albumen  and  attacks  of  edema.  While 
Benczur  and  Czatary,  and  v.  Jaksch  ^  believe  that  the  hydremia  is  not 
proportionate  to  the  edema,  yet  Bogdanow,  and  Stintzing  and  Gum- 
precht  have  shown  a  positive  connection  between  hydremia  and  edema, 
and  have  noted  an  improvement  in  the  blood  following  improvement 
in  general  symptoms. 

The  relatively  high  Hb-index  is  apparently  the  natural  result  of  a 
loss  of  albumen  which  affects  principally  the  serum.  The  gravity  of 
the  red  cells  has  been  found  uniformly  high  by  most  analysts  since 
the  time  of  Scherer. 

Grave  or  pernicious  anemia  develops  in  a  small  proportion  of  cases 
of  chronic  parenchymatous  nephritis,  and  appears  at  times  to  result 
directly  from  nephritis.  It  must  be  referred  to  the  repeated  losses  of 
albumen  from  the  blood  and  to  the  general  disturbance  of  nutrition,  but 
it  is  probable  that  the  very  severe  grades  of  anemia  result  from  the 
combined  effects  of  lesions  in  several  viscera,  including  chronic  gas- 
tritis, cirrhosis  of  liver,  arteriosclerosis,  etc. 

Chemistry. — Chemical  analysis  gives  the  clearest  insight  into  the 
changes  in  the  blood  of  nephritis.  The  specific  gravity  is  regularly 
reduced.  Peiper^  found  a  gravity  of  1.026  in  a  very  anemic  child, 
but  after  marked  improvement  four  weeks  later,  the  gravity  was  1.055. 
Similar  variations,  usually  between  these  limits,  are  reported  by  various 
observers.  The  changes  in  the  serum  demonstrated  by  the  older  ob- 
servers have  been  verified  by  many  later  studies.  The  gravity  of 
the  serum  is  much  reduced  (as  low  as  1.013,  Bostock),  and  its  volume 
remains  high.  While  considerable  relation  has  been  found  to  exist 
between  the  changes  in  the  blood  and  the  albuminuria  and  edema 
(Stintzing,  Gumprecht,  Bogdanow),  the  immediate  effects  of  transudates 
and  albuminuria  are  not  always  evident,  (v.  Jaksch.)  Hammar- 
schlag,  who  found  the  gravity  of  the  serum  between  1.018  and  1.030, 
concluded  that  edema  has  more  effect  upon  the  gravity  of  the  serum  than 
has  albuminuria ;  and  that  when  edema  is  absent  the  gravity  of  the 
serum  is  usually  about  normal. 

The  leucocytes  in  chronic  nephritis  are  usually  normal  or  subnormal 
in  number.  Cabot  found  no  leucocytosis  in  31  of  40  unclassified  cases, 
while  in  14  of  19  uremic  cases  there  was  leucocytosis,  reaching  44,- 
000  in  one  eclamptic  patient.  Other  reports  show  similar  variations, 
and  it  is  evident  that  the  behavior  of  the  leucocytes  in  chronic 
nephritis  depends  upon  accidental  conditions  and  complications. 

Chronic  Interstitial  Nephritis.  (Contracted  Kidney.) — The  ab- 
sence of  edema  and  marked  albuminuria  in  cases  of  chronic  nephritis 
without  exudation  allows  the  blood  to  remain    practically  normal,  at 


364  LUNGS,   HEART,   KIDNEYS. 

least  during  the  latent  progress  of  the  disease.  Many  patients  are 
carried  oiF  by  acute  uremia  and  other  terminations  of  interstitial  ne- 
phritis before  the  blood  is  markedly  altered.  If  at  any  time  in  the 
progress  of  the  disease  there  are  exacerbations  marked  by  exudation, 
albuminuria,  and  edema,  the  blood  suffers  for  a  time  as  in  chronic  ne- 
phritis of  more  distinctly  exudative  type.  After  the  exudative  period 
the  blood  is  partially  restored,  but  a  certain  grade  of  chlorotic  anemia 
is  apt  to  persist. 

That  chronic  nephritis  may  run  its  course  without  giving  notable  changes 
in  the  blood,  or  indeed  any  other  pronounced  symptoms,  is  a  well  attested 
fact,  of  which  the  writer  has  seen  at  autopsy  at  least  one  instance.  This 
subject  was  an  able-bodied  policeman  dying  of  acute  colitis,  whose  kidneys 
were  shrunken  to  an  extreme  degree.  The  blood  and  urine  were  normal 
shortly  before  death. 

On  the  other  hand,  very  severe  grades  of  anemia,  usually  of  micro- 
cytic type,  are  sometimes  associated  with  chronic  diffuse  nephritis  with- 
out exudation.  Some  of  these  cases  are  partly  referable  to  lead  poi- 
soning, which  has  initiated  the  renal  lesion  and  damaged  the  blood. 
In  others,  there  is  advanced  arterio-sclerosis  with  frequent  hemorrhages 
from  the  nose,  kidneys,  or  other  regions.  In  still  others  no  reason- 
able explanation  of  the  anemia  is  to  be  found. 

Grawitz  recognizes  two  stages  in  this  disease,  one  in  which  the  heart  and 
circulation,  and  the  blood,  are  normal  and  a  second  in  which  compensation 
fails  in  the  hypertrophied  heart  and  the  blood  suffers  the  same  changes  as  in 
uncompensated  valvular  disease.  The  importance  of  the  condition  of  the 
heart  in  determining  the  blood  changes  in  nephritis  is  very  great  and  has 
already  been  considered  in  the  references  to  edema  and  cyanosis,  but  failure 
of  the  left  ventricle  with  feeble  pulse  is  more  common  with  the  large  white 
than  with  the  small  contracted  kidneys.  The  writer  is,  therefore,  unable  to 
recognize  the  above  stages  in  the  course  of  the  contracted  kidney,  finding 
them  more  evident  in  the  cases  of  chronic  diffuse  nephritis  with  exudation, 
and  in  patients  with  albuminuria  and  edema. 

Acute  Nephritis. — The  changes  in  the  blood  in  acute  nephritis  with 
albuminuria  and  edema  resemble  those  of  the  same  type  of  chronic 
nephritis.  Peiper  found  no  diminution  in  specific  gravity  in  an  acute 
case.  Laache  and  Bogdanow  observed  more  rapid,  severe,  and  more 
variable  changes  in  the  acute  than  in  the  chronic  cases,  while  v. 
Jaksch  concluded  that  in  both  forms  the  changes  were  about  equally 
variable.  Hayem  found  no  considerable  loss  of  red  cells  except  in 
hemorrhagic  cases.  Many  other  isolated  reports  show  all  but  the  very 
severe  grades  of  anemia  developing  within  a  few  weeks,  sometimes 
very  rapidly. 

Leucocytosis  (maximum  22,000)  has  been  observed  in  a  considerable 
proportion  of  cases  by  Hayem,  Sadler,  and  Cabot,  the  latter  author  re- 
ferring the  persistent  increase  to  loss  of  blood  by  the  kidney. 

None  of  these  observers  has  attempted  to  connect  the  behavior  of  the 
leucocytes  with  the  character  of  the  lesion  in  the  kidneys.  It  would  seem 
that  the  productive  inflammation  could  run  a  fatal  course  without  leucocy- 
tosis, that  simple  acute  exudative  nephritis  might  be  accompanied  by  a 


DISEASES  OF  THE  KIDNEY.  365 

moderate  increase  of  white  cells,  and  that  acute  idiopathic  or  secondary 
purulent  nephritis  must  nearly  always  be  accompanied  by  marked  leucocy- 
tosis.  Unfortunately  there  are  no  reports  at  hand  on  which  to  base  these 
conclusions.  Profuse  hemorrhage,  uremic  attacks,  and  complicating  infec- 
tions, may  be  responsible  for  occasional  leucocytosis,  but  Sadler's  negative 
cases  show  that  much  albumen,  many  granular  casts,  and  blood  cells,  may  be 
present  in  the  urine  when  the  leucocytes  in  the  blood  are  not  increased. 

Uremia.  Chemistry. — Very  numerous  chemical  analyses  of  the 
blood  in  uremia  have  failed  as  yet  to  demonstrate  the  true  nature  of 
this  intoxication.  Urea  in  the  blood  was  believed  by  Frerichs  to  be 
the  particular  toxic  agent  in  uremia,  and  although  this  principle  has 
been  demonstrated  in  abnormal  quantities  in  the  blood  of  uremic  coma 
by  Spiegelberg,  Hoppe-Seyler,  Bartels,  and  others,  it  was  shown  by 
Landois  that  intravenous  injections  or  local  applications  to  the  medulla 
of  large  quantities  of  urea  exert  no  toxic  influence.  Neither  has  its  de- 
rivative, ammonium  carbonate,  been  found  in  the  blood,  nor  shown  to 
exert  a  toxic  influence  on  the  nervous  system  (Kuhne,  Strauch).  Kee- 
ATININ,  believed  by  Schottin  and  Perls  to  be  the  active  agent,  has  like- 
wise been  set  aside  although  this  substance  is  increased  in  the  blood 
of  uremic  subjects.  Potassium  has  been  found  in  considerable  excess 
in  the  blood  by  Feltz  and  Ritter,  and  by  Astaschewsky,  who  regard 
uremia  as  a  form  of  potassium  poisoning.  Although  Sneyers  and  Hor- 
baczewsky  failed  to  find  an  excess  of  potash  salts  in  eclamptic  and 
uremic  subjects,  this  theory  has  received  more  recent  support  frow 
Bouchard,  Roger,  Rovighi,  and  others,  who  oflFer  evidence  to  shom 
that  potassium  is  one  of  several  poisonous  substances  which  accumu- 
late in  the  blood  in  uremia.  Limbeck  has  shown,  however,  that  while 
an  excess  of  potash  can  be  obtained  from  the  blood  of  uremic  dogs, 
he  could  get  no  such  excess  if  the  blood  was  examined  before  death. 

Diminished  alkalescence  was  first  noted  in  uremic  blood  by  v. 
Jaksch,^  and  subsequently  by  Peiper,^  Rumpf,  Mya  and  Tassinari, 
Limbeck,  and  others,  who  have  shown  that  the  alkalescence  diminishes 
greatly  on  the  approach  of  uremic  symptoms.  The  attempt  to  estab- 
lish this  theory  of  acid  intoxication  has,  however,  not  been  successful. 
Although  uric  acid  may  be  in  excess  in  uremia,  it  is  also  quite  as  much 
increased  in  many  other  conditions.  Fatty  acids,  and  phosphoric  acids 
were  not  found  in  excess  by  Limbeck,  who  indeed  was  unable  to  de- 
monstrate a  deficiency  of  CO2  in  all  cases  of  experimental  uremia. 
Diminished  alkalescence  appears  more  probably  to  be  only  a  secondary 
condition  of  the  blood  in  uremia. 

The  present  tendency  is  to  regard  the  uremic  seizure  as  the  result  of 
toxic  action  of  a  variety  of  nitrogenous  metabolic  products  which  are 
supposed  to  be  retained  in  the  system  or  at  times  thrown  off"  in  excess 
in  the  urine.  Bouchard  and  others  have  isolated  from  the  urine  a 
variety  of  toxic  principles,  including  ptomaines  and  urotoxines,  some  of 
which  produce  convulsions,  others  are  narcotic,  while  still  others  lower 
temperature,  contract  the  pupil,  or  produce  salivation.  Although  the 
actual  existence  of  these  principles  has  been  denied  (Stadthagen),  and 


366  LUNGS,   HEART,   KIDNEYS. 

the  urine  has  not  always  been  found  so  toxic  as  Bouchard  claims  it  to 
be  (Fleischer),  the  autotoxic  theory  is  generally  regarded  as  approach- 
ing most  nearly  to  the  true  explanation  of  uremia.  One  of  the  chief 
objections  to  it  consists  in  the  fact  that  uremic  attacks  frequently  arise 
at  periods  when  the  excretion  of  urine  is  much  improved. 

Bibliography. 

Diseases  of  Heart,  Lungs,  Kidneys. 

Astaschewsky.     St.  Petersb.  med.  AVoch.,  1881,  No.  27. 
Bamberger.     Wien.  klin.  Woch.,  1888,  No.  1. 
Banhoher.     Cent.  f.  inn.  Med.,  1894,  No.  23. 
Bartels.     Ziemsenn's  Handb.,  Bd.  IX.,  p.  1. 
Benczur,  Czaiary.     Deut.  Archiv  klin.  Med.,  Bd.  46,  p.*478. 
Biernacki.     Cent.  f.  inn.  Med.,  1895,  No.  14. 
Billings.     N.  Y.  Med.  Jour.,  Vol.  65,  p.  691. 
Bogdanow.     St.  Petersb.  med.  Woch.,  1875. 
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CHAPTER  XXII 

MALIGNANT   TUMORS. 

CARCINOMA. 

The  impression  obtained  by  individual  observers  of  the  effect  of 
carcinoma  upon  the  blood  has  largely  depended  upon  the  class  of  cases 
encountered. 

In  active  hospital  wards  the  cases  are  usually  advanced,  cachexia  is 
distinct,  and  routine  examination  of  the  blood  shows  as  a  rule,  marked 
reduction  of  red  cells,  low  Hb-index,  and  moderate  but  distinct  leuco- 
cytosis.  In  dispensaries  the  earlier  stages  of  the  disease  are  encoun- 
tered, cachexia  and  palpable  tumors  are  not  always  noted,  many  tenta- 
tive diagnoses  stand  with  positive  cases,  and  the  blood  very  often  fails 
to  show  any  pronounced  alteration. 

In  a  considerable  group  of  cases  the  progress  of  the  usual  anemia  is 
interrupted,  however,  for  unknown  reasons,  and  while  the  patient 
emaciates,  the  blood  appears  to  maintain  its  standard.  Hampeln, 
Neubert,  Dehio,  and  others,  therefore  speak  of  an  anemic,  and  a 
marantic  type  of  carcinoma.  Neubert's  cases,  5  esophageal  and  4 
gastric,  were  especially  adapted  to  illustrate  the  differences,  but  both 
types  may  occasionally  be  seen  in  other  forms  of  the  disease,  e.  g.,  can- 
cer of  uterus. 

Many  careful  studies  have  shown  that  in  the  earlier  recognizable  stages 
of  the  disease,  and  in  somewhat  more  advanced  phases  of  visible  growths, 
the  blood  remains  practically  normal.  Few  published  series,  how- 
ever, show  so  large  a  proportion  of  cases  with  red  cells  above  4 
millions  as  does  Cabot's,  in  which  34  of  72  cases  of  carcinoma  of 
stomach  gave  over  4  million,  and  19  over  5  million  red  cells.  Yet 
this  series  may  well  serve  to  emphasize  the  fact  that  carcinoma  com- 
monly exists  in  otherwise  healthy  subjects,  and  for  a  time  fails  to  reduce 
the  number  of  red  cells.  The  significance  of  a  normal  red  cell  count  is 
of  course  limited  by  the  fact  that  in  many  situations  the  growth  tends 
to  retard  the  ingestion  and  absorption  of  fluids  and  thus  to  concentrate 
the  blood.  Yet  in  some  instances  the  malignant  growth,  like  tubercu- 
losis, appears  to  exert  some  obscure  concentrating  influence  on  the  blood, 
and  even  at  death,  although  the  body  is  emaciated,  the  blood  may  be 
unusually  deep  red. 

Osterspey  found  5  millions  of  red  cells  and  98  percent  of  Hb  three  months 
after  the  symptoms  of  a  gastric  cancer  were  developed,  w^ile  in  a  patient  who 
had  lost  100  pounds  weight  within  a  year  from  gastric  cancer,  he  found 
4,544  red  cells  and  82  percent  of  Hb.     Laache,  who  noted  the  same  apparent 


CARCINOMA.  369 

immunity  of  the  blood  against  the  effects  of  a  bleeding  uterine  carcinoma, 
concluded  that  there  is  an  individual  insusceptibility  to  the  effects  of  malignant 
tumors. 

It  is,  nevertheless,  true  tliat  in  the  majority  of  carcinomata  the  appear- 
ance of  cachexia  is  accompanied  by  a  corresponding  oligocythemia. 
Cancers  of  the  stomach  are  among  the  more  active  in  reducing  red 
cells,  and  some  of  them,  even  while  remaining  of  small  size,  lead  to 
the  changes  of  pernicious  anemia.  Grawitz  counted  only  500,000  red 
cells  in  one  extreme  case  of  gastric  cancer.  Of  complications,  hemor- 
rhage and  ulcerations  usually  affect  the  red  cells  promptly.  Rapid 
growth  and  numerous  metastases  also  have  a  similar  tendency  but  prob- 
ably less  marked. 

Morphologically,  the  red  cells  in  carcinoma,  while  presenting  the 
usual  degenerative  changes  of  secondary  anemia,  do  not  show  any 
special  peculiarities.  The  usual  changes  are  those  of  well-marked 
chlorotic  anemia  with  considerable  deficiency  of  Hb,  but  with  mod- 
erate changes  in  size  and  shape,  Grawitz  found  granular  degeneration 
of  many  cells  in  10  cases  of  cancer  of  the  stomach  or  esophagus,  but 
none  in  two  cases  of  uterine  cancer.  The  writer  finds  that  in  those 
oases  in  which  the  appearance  of  the  blood  suggests  pernicious  anemia, 
the  deficiency  of  Hb,  even  in  the  majority  of  megalocytes,  is  nearly 
always  quite  distinct. 

Mouisset  has  already  called  attention  to  this  fact,  finding  the  Hb-index 
in  these  cases  to  be  quite  as  low  as  in  chlorosis.  In  a  case  of  Daland's,  the 
hematocrit  gave  rather  fewer  red  cells  than  the  hematocytometer,  but  in  per- 
nicious anemia  the  volume  of  the  red  cells  is  usually  much  above  normal. 
(Cf.  Moraczewsky.) 

Nucleated  red  cells  are  commonly  seen  when  the  anemia  is  severe, 
and  in  some  cases  of  gastric  cancer  they  may  be  extremely  abundant. 
Usually  these  cells  are  of  normal  size,  but  megalocytes  appear  in  the 
severest  cases.  It  has  been  suggested  that  the  predilection  for  the 
bone  marrow  as  the  seat  of  metastases  is  responsible  for  the  large  num- 
ber of  nucleated  red  cells  seen  with  many  advanced  carcinomata. 
(Epstein.)  They  are  sometimes  seen,  however,  in  the  early  stages  of 
the  growth  and  when  anemia  is  slight. 

The  Hemog'lobm  begins  to  suffer  much  earlier  than  the  number  of 
red  cells.  The  writer  has  never  seen  an  uncomplicated  visceral  carci- 
noma, positively  identified,  which  had  failed  to  reduce  the  percentage  of 
Hb  and,  barring  clear  cases  of  polycythemia,  can  find  none  fully  re- 
ported in  the  literature.  Fully  normal  Hb  appears  to  be  a  very  re- 
liable negative  indication  against  carcinoma  at  any  stage.  There  are 
however  reports  of  90-100  percent  of  Hb  in  cases  with  increased 
numbers  of  red  cells,  and  the  loss  is  doubtless  slight  during  the  early 
stages  of  most  cases.  Usually  a  malignant  epithelial  tumor  rather 
promptly  reduces  the  Hb,  so  that  during  the  greater  part  of  its  prog- 
ress the  Hb  is  below  75  percent.  In  Bierfreund's  and  Reinbach's 
series  of  57  surgical  cases,  it  varied  between  18  and  80  percent,  while 
few  registered  over  70  percent,  and  in  comparison  with  benign  tumors 
24 


370  MALIGNANT  TUMORS. 

the  Hb  in  cancer  was  distinctly  lower.  After  operation  the  restora- 
tion of  the  Hb  required  about  a  week  longer  with  malignant  than  with 
benign  tumors,  and  the  restoration  was  never  quite  complete.  With 
internal  visceral  carcinomata  the  Hb  has  usually  been  found  even 
lower,  but  there  are  numerous  exceptions  to  this  rule,  usually  de- 
pending on  the  site  of  the  tumor. 

A  rather  uniformly  low  percentage  of  Hb  in  visceral  carcinomata  was  found 
by  Laker,  Eiclihorst,Haberlein,  Laache,  Dehio,  Leichtenstern,  Moraczewsky, 
and  others,  while  Sailer's  and  Taylor's  series  of  21  cases  gave  the  unusually 
low  average  of  25  percent.  Osterspey's  and  Cabot's  cases  were  somewhat 
higher,  often  approaching  the  normal.  Yet  Eaberlin  concluded  that,  in  steno- 
sis of  the  pylorus,  cancer  is  contradicted  if  the  Hb  is  over  60  percent. 

The  Hb-index  is  uniformly  low.  In  some  cases  it  has  approached 
that  of  chlorosis,  and  although  it  is  usually  somewhat  higher,  carci- 
noma offers  a  closer  resemblance  to  chlorosis  in  this  respect  than  almost 
any  other  cause  of  secondary  anemia.  As  the  disease  progresses  the 
anemia  itself  becomes  more  severe,  and  when  chronic  cachexia  has  been 
long  established  the  blood  shows  the  characters  of  secondary  pernicious 
anemia,  with  variations  in  the  size  of  the  cells  and  increasing  Hb-index. 
Yet  with  rare  exceptions  the  relatively  great  loss  of  Hb  remains  char- 
acteristic. 

Leichtenstern  2  long  since  called  attention  to  a  rapid  increase  of  Hb,  to 
100  percent  or  more,  seen  in  some  cases  of  gastric  cancer  shortly  before  death, 
and  to  the  tarry  appearance  of  the  blood  at  autopsy.  Patrigeon,  in  a  gastric 
case,  found  the  red  cells  normal  nine  days  before  death.  The  writer  has  ob- 
served this  condition  in  patients  who  had  failed  to  take  any  food  and  little 
drink  for  some  days  before  death. 

Special  Factors  in  the  Anemia  of  Carcinoma. — The  special  con- 
ditions leading  to  severe  anemia  are  numerous,  and  some  are  obscure. 
Hemorrhage  and  ulceration  are  among  the  frequent  complications  recog- 
nized as  rapidly  impoverishing  the  blood,  but  occasional  escape  from 
their  natural  effects  has  been  recorded.  The  site  of  the  tumor  may 
be  such  as  to  interfere  with  nutrition,  as  do  some  gastric  carcinomata. 
A  previous  condition  of  anemia  may  exist  before  the  development  of 
the  cancer,  as  when  a  round  ulcer  of  the  stomach  becomes  malignant. 
Rapidly  forming  and  numerous  metastases  are  usually  associ- 
ated with  severe  and  progressive  anemia,  but  there  are  numerous  ex- 
ceptions to  this  rule,  some  emaciated  subjects  showing  a  tendency  to 
concentration  of  the  blood.  In  two  cases  with  extensive  bone  meta- 
stasis the  writer  found  only  moderate  anemia  and  but  few  nucleated 
red  cells.  Individual  idiosyncrasy  appears  to  influence  the  course  of 
the  cachexia  both  favorably  and  unfavorably.  The  histological  char- 
acter of  the  tumor  appears  to  have  no  relation  to  the  anemia  except  in 
so  far  as  the  structural  type  favors  hemorrhage  or  ulceration.  The 
chronic  toxemia  of  carcinoma  may  apparently  affect  the  blood  in  a 
variety  of  ways.  Muller  offers  evidence  to  show  that  the  blood  of 
cancerous  patients  contains  toxic  principles  which  destroy  albumens 
and  diminish  alkalescence.     Grawitz  injected  the  alcoholic  extract  of 


CARCINOMA.  371 

a  cancerous  tumor  into  rabbits,  and  finding  a  considerable  loss  of 
gravity  and  dry  residue,  concluded  that  the  toxines  of  carcinoma  tend 
to  dilute  the  blood  by  inducing  excessive  flow  of  lymph. 

Maragliano  has  demonstrated  an  increased  globulicidal  activity  of  the 
serum  in  carcinoma. 

The  Leucocytes. — Leucocytosis  in  carcinoma  was  very  early  recog- 
nized as  a  nearly  constant  condition,  having  been  observed  post-mortem 
by  Andral,  in  1823,  and  in  the  living  blood  by  Lucke,  and  by  Virchow, 
about  1867.  The  white  cells  were  long  regarded  as  derivatives  of  the 
tumor,  an  error  which  was  slowly  relinquislied  when  leucocytes  were 
submitted  to  more  careful  classification  by  Schultze. 

That  the  carcinomatous  process  has  in  itself  any  capacity  to  draw 
leucocytes  to  the  blood  may  still  be  doubted,  although  the  edges  of  the 
tumor  are  always  inflamed  and  adjacent  lymph  nodes  invariably  show 
inflammatory  hyperplasia  before  metastasis.  In  tumors  of  ordinary 
size  and  character  this  inflammatory  process  is  usually  too  limited  to 
aflFect  the  leucocytes,  but  with  very  large  growths,  as  in  the  liver,  lung, 
uterus,  etc.,  the  frequency  of  leucocytosis  without  complications,  indi- 
cates that  a  large  actively  growing  tumor,  merely  through  its  local 
irritation,  may  induce  leucocytosis.  Thus  Hayem  saw  a  leucocytosis 
of  21,700  disappear  after  the  removal  of  a  scirrhus  of  the  breast,  only 
to  return  again  with  the  recurrence  of  the  tumor.  Hayem  believes 
that  recurrences  may  be  predicted  by  the  appearance  of  a  gradually 
increasing  leucocytosis.  On  the  other  hand,  advanced  cachexia  may 
exist  with  hypoleucocytosis.  (Sailer,  Taylor.)  Rapid  growth  is  much 
more  eff^ective  in  raising  the  number  of  leucocytes,  probably  by  excit- 
ing more  active  local  reaction,  and  by  more  sudden  disturbance  of 
function  in  the  part  affected. 

Superficial  ulceration,  or  other  inflammatory  complications,  are  the 
usual  causes  of  well-marked  leucocytosis  with  carcinoma.  Hemorrhages 
usually  accompany  ulceration,  and  add  distinctly  to  the  excess  of  leu- 
cocytes commonly  seen  in  bleeding  and  ulcerating  tumors. 

The  type  of  the  tumor  has  a  distinct  relation  to  leucocytosis,  which, 
however,  cannot  always  be  traced.  The  cellular  carcinomata  tend  to 
irritate,  ulcerate,  soften,  and  bleed,  while  fibrous  tumors  are  of  slow 
growth,  and  non-vascular.  The  writer  has  observed  two  very  large 
gelatinous  carcinomata  of  the  peritoneum  without  leucocytosis.  The 
diffuse  cancers  of  the  stomach  regularly  excite  less  increase  of  leucocytes 
than  does  the  adenomatous  type. 

The  situation  of  the  tumor  often  determines  the  frequency  of  leucocy- 
tosis, from  special  liability  to  ulceration  or  bleeding.  Many  cancers 
of  the  stomach  and  uterus  illustrate  this  rule.  Epithelioma  of  the 
esophagus  rarely  induces  leucocytosis  unless  there  is  extreme  ulcera- 
tion and  extension. 

Unusually  high  leucocytoses  are  reported  in  a  case  of  carcinoma  of  thyroid, 
by  Hayem,  and  in  cases  of  unidentified  tumors  of  the  kidney,  by  Cabot,  and 
in  several  cases  of  gastric  cancer,     (q.  v.) 

Leucocytosis  in  Cancek  of  the  Breast. — Alexander  found  an  average 


372  MALIGNANT  TUMORS. 

of  11,400  leucocytes,  and  variations  between  2,360  and  21,700,  in  14  cases  of 
scirrhus.  In  three  cases  of  alveolar  carcinoma  with  extensive  metastasis  the 
leucocytes  numbered  10,075,  11,625,  and  12,400.  Hayem  (p.  947)  found  a 
distinct  reduction  of  leucocytes  following  4  operations  for  scirrhus. 

It  will  be  seen  that  the  leucocytosis  of  carcinoma  is  referable  largely 
to  complications,  and  these  complications  are  such  as  appear  very  con- 
stantly in  rapid  or  advanced  cases.  These  conclusions  accord  with 
the  o-eneral  experience  that  most  cases  of  well-established  carcinoma 
are  accompanied  by  leucocytosis.  The  great  variety  of  these  compli- 
cations render  it  unwise  to  draw  any  narrow  diagnostic  conclusions 
from  the  presence  or  absence  of  leucocytosis. 

The  varieties  of  leucocytes  in  the  blood  in  carcinoma  are  found  in 
much  the  same  proportions  as  in  other  forms  of  cachectic  leucocytosis. 
With  marked  leucocytosis  the  polynuclear  cells  usually  form  a  high 
percentage,  77-89  percent  (Reinbach),  74-96  percent  (Cabot).  Yet 
in  a  case  of  the  pernicious  anemic  type  of  gastric  cancer  Sailer  and 
Taylor  reported  45,000  leucocytes,  of  which  46  percent  were  mono- 
nuclear, and  these  authors  found  the  large  mononuclear  cells  to  regu- 
larly exceed  the  small  lymphocytes.  Unusually  high  leucocytoses  have 
been  reported  in  the  anemic  type  of  gastric  cancer  by  several  other  ob- 
servers, some  instances  of  which  apparently  represent  ante-mortem  leu- 
cocytosis, while  in  others  the  excess  was  noted  long  before  death. 
Eisenlohr,  Mayer,  and  Lebert  reported  a  ratio  of  one  white  to  fifty  red 
cells ;  Potain,  1-48  ;  Welch,  1-20. 

Braun  has  described  a  case  of  cancer  of  prostate  with  pernicious 
anemia  (1  million  red  cells,  10,700  leucocytes)  in  which  the  majority 
of  white  cells  were  lymphocytes,  but  a  few  eosinophile  myelocytes  were 
present.  Eosins  usually  persist  in  low  normal  proportions,  from  1.2, 
1.5,  to  2  percent.     (Cabot,  Sailer,  Taylor,  Reinbach.) 

Myelocytes  are  found  in  a  large  proportion  of  cachectic  cases,  and 
sometimes  in  considerable  numbers.  They  are  most  abundant  in  the 
ante-mortem  leucocytoses,  when  the  excess  of  various  forms  of  leuco- 
cytes, with  normoblasts  and  anemic  red  cells,  may  suggest  leukemia. 
Sailer  and  Taylor  found  9.3  percent  of  these  cells  in  a  very  anemic  case. 
Leucocytes  holding  fragments  of  red  cells  or  showing  various  degen- 
erative changes  are  described  by  Hayem  and  Escherich. 

Specific  Gravity. — The  specific  gravity  of  the  blood  in  well  estab- 
lished carcinomatous  cachexia  is  remarkably  low.  This  fact  is  illus- 
trated in  Dieballa's  series  in  which  cases  of  gastric  cancer  with  1|  to  2 
million  cells  show  the  same  gravity,  1.030-1.032,  as  cases  of  pernicious 
anemia  with  only  .5  to  1  million  cells.  Peiper  also  found  very  low 
gravity  in  4  advanced  cases,  while  the  lowest  reports  are  those  of 
Moraczewsky,  1.012  and  1.016.  While  Hammarschlag  obtained  nearly 
normal  gravity  for  the  serum  in  these  cases,  Grawitz,  Strauer,  and  v. 
Jaksch  found  exceptionally  low  percentages  of  dry  residue  and  albu- 
men, indicating  that  in  carcinoma  the  albumens  of  the  serum  suffer  in 
a  peculiar  degree.     Biernacki  located  the  marked  loss  of  albumens 


SARCOMA.  373 

principally  in  the  red  cells,  but  concluded  that  the  iron  is  not  always 
markedly  diminished. 

In  the  less  advanced  cases  of  carcinoma  the  gravity  of  the  blood 
does  not  differ  from  that  of  other  secondary  anemias.  (Devoto, 
Schmaltz,  Scholkoff,  Hammarschlag,  Stintzing,  Gumprecht.) 

The  alkalescence  of  the  blood  has  been  found  considerably  dimin- 
ished, as  in  other  forms  of  secondary  anemia.  Klemperer  and  v.  Lim- 
beck, Peiper  and  Rumpf,  and  Moraczewsky,  using  different  methods, 
found  very  low  grades  of  alkalescence  in  advanced  cases,  v.  Noorden 
refers  this  change  to  the  liberation  of  sulphuric,  phosphoric,  acetic, 
and  oxybutyric  acids,  from  the  destruction  of  albumens. 

An  excess  of  sugar  was  found  by  Freund  in  a  series  of  cases,  and 
while  Trinkler  confirmed  these  results,  Matrai  had  previously  shown 
that  it  is  neither  constant  in,  nor  peculiar  to,  carcinoma. 

A  peculiar  form  of  coma,  described  by  v.  Jaksch  ^  and  others,  some- 
times terminates  the  course  of  gastric  cancer,  and  has  been  referred  by 
Senator  to  an  obscure  toxemia  resulting  from  disturbed  metabolism. 
Herter's  demonstration  of  a  great  excess  of  bases  over  acids,  and  a  great 
diminution  of  ammonia,  in  the  urine  in  chronic  gastritis,  strongly  indi- 
cates that  an  acid  intoxication  exists  in  these  cases,  as  in  diabetic  coma. 
(See  Chronic  Gastritis.) 

SARCOMA. 

The  early  changes  in  the  blood  in  sarcoma  closely  resemble  those  of 
carcinoma,  but  some  comparison  of  details  will  be  of  interest. 

Red  Cells. — The  usual  variations  in  the  progress  of  anemia  are  to 
be  observed,  including  the  absence  of  oligocythemia,  or  even  the  pres- 
ence of  polycythemia  in  the  early  stages  (Alexander,  Reinbach,  Cabot), 
and  very  slow  or  very  rapid  impoverishment  of  the  blood  according  to 
the  rate  of  growth  and  character  of  the  complications. 

In  the  cases  recorded  by  Hayem,  Alexander,  Laker,  Limbeck,  Sad- 
ler, Rieder,  Reinbach,  Bierfreund,  Cabot,  it  is  impossible  to  find  any 
uniform  difference  in  the  grade  of  anemia  from  that  observed  with  car- 
cinoma, and  this  conclusion  accords  with  the  writer's  experience. 
Reinbach,  however,  finding  only  4  normal  blood  specimens  in  20  cases 
of  sarcoma,  and  6  among  16  cases  of  carcinoma,  concluded  that  the 
anemia  of  sarcoma  is  usually  greater  than  in  carcinoma. 

There  are  also  some  pathological  grounds  on  which  Reinbach's  con- 
clusions may  be  supported,  in  the  special  relation  of  sarcomatous 
growths  to  blood  vessels  and  marrow,  their  greater  tendency  to  hem- 
orrhage and  degeneration,  and  their  more  frequent  association  with 
febrile  processes,  leucocytosis,  or  even  leukemia. 

The  lowest  number  of  red  cells  observed  appears  to  be  that  recorded 
by  Hayem  at  663,400,  while  Rieder  found  only  6  percent  of  Hb  (?) 
in  a  dying  subject.  Limbeck  says  that  normal  blood  is  more  fre- 
quently found  with  early  sarcomata  than  with  early  carcinomata,  while 
Reinbach  has  never  seen  in  early  carcinoma  the  extreme  alterations  of 


374  MALIGNANT  lUMORS. 

the  blood  which  he  referred  to  an  early  sarcoma.  Alexander  reports 
an  extensive  osteosarcoma  of  sternum  and  vertebrae  with  over  6  mil- 
lion red  and  52,000  white  cells,  and  in  his  and  other  series  of  osteo- 
sarcoma the  average  anemia  is  not  extensive.  In  Cabot's  16  cases  the 
averao-e  of  red  cells  was  4.4  millions,  with  extremes  between  2.6  and 
6.2  millions. 

Nucleated  red  cells  are  rather  less  common  than  in  carcinoma.  The 
chano-es  of  progressive  pernicious  anemia  were  present  in  the  blood  in 
cases  of  osteosarcoma  reported  by  Grawitz,  Ehrlich,  Hosier  and  Gast, 
Fede,  and  Hausler. 

Leucocytes. — The  relatively  greater  frequency  and  extent  of  leuco- 
cytosis  in  sarcoma  appears  to  be  the  most  striking  difference  in  the 
blood  between  the  two  groups  of  malignant  tumors.  The  great  major- 
ity of  sarcomata  when  first  observed  have  shown  a  distinct  leucocytosis, 
which  moreover  tends  to  persist  and  often  to  increase,  with  the  advance 
of  the  tumor,  till  at  death  the  upper  limits  of  inflammatory  leucocytosis 
are  frequently  reached.  Martin  and  Matthewson  have  described  leu- 
cocytosis of  this  extreme  type  and  pointed  out  some  of  the  difficulties 
in  diagnosis  which  may  result  therefrom. 

Indeed,  there  are  several  recorded  instances  in  which  the  lymphocy- 
tosis of  sarcoma  terminated  in  lymphatic  leukemia.  The  writer  observed 
such  a  case  in  1899,  and  others  have  been  reported  by  Palma,  Sadler, 
and  Strauss. 

Palma' s  and  Sadler's  cases  were  round -celled  sarcomata.  In  the  writer's 
case  various  parts  of  the  tumor  and  its  metastases  showed  gradations  be- 
tween round  and  large  spindle-celled  sarcoma.  The  recorded  transforma- 
tions of  pseudo-leukemia  into  leukemia  are  doubtless  of  similar  significance. 
(Fleischer,  Penzoldt,  v.  Jaksch,2  Westphal,  Hosier,  Senator.) 

The  types  of  leucocytes  show  greater  variety  in  sarcoma  than  in  car- 
cinoma. The  majority  of  leucocytoses  being  of  inflammatory  origin,  an 
excess  of  polynuclear  cells  is  the  rule,  and  even  with  a  normal  number 
the  proportion  of  these  cells  may  be  excessive.  Lymphocytosis, 
though  not  relatively  frequent  with  sarcomata,  has  at  times  reached 
the  grade  of  lymphatic  leukemia,  as  in  the  cases  mentioned.  In  lym- 
phosarcoma, as  in  pseudo-leukemia,  the  lymphocytes  are  not  usually 
excessive,  and  in  many  cases  are  very  scanty.  Eosinophilia  has 
been  regarded  by  Neusser  as  one  of  the  diagnostic  signs  of  sarcoma  of 
bone  marrow.  A  marked  and  persistent  excess  of  these  cells,  48  per- 
cent, was  found  in  one  of  Reinbach's  cases  of  lymphosarcoma  compli- 
cated by  phthisis,  and  bone  metastases  were  found  at  autopsy.  Three 
other  cases,  without  autopsy,  showed  from  8  to  12  percent  of  eosins,  but 
these  cells  were  normal  in  most  of  his  cases,  and  absent  in  five. 

There  seems  to  be  some  diff'erence  in  the  extent  of  leucocytosis  ob- 
served in  various  types  of  sarcoma.  In  16  cases  of  osteosarcoma  col- 
lected by  Cabot  from  several  authors,  the  average  was  17,000,  in  12 
lymphosarcomata  20,000,  and  in  7  melanotic  sarcomata  25,100.  With- 
out further  details  than  the  reports  of  these  cases  furnish  the  signifi- 
cance of  these  data  is  limited.     The  greater  leucocytosis  of  melanotic 


BIBLIOGRAPHY.  375 

sarcoma  accords  with  its  recognized  malignancy,  and  some  marked 
leucocytoses  observed  by  Alexander  and  Limbeck  (52,000,  32,000)  in 
osteosarcomata  may  perhaps  go  with  myeloid  tumors,  which  are  more 
malignant  than  the  periosteal. 

Myelocytes  were  noted  in  Reinbach's  case,  cited  above,  which  also 
showed  eosinophilia.  Cabot  found  7  percent  of  large  and  small  myelo- 
cytes in  a  case  of  general  sarcomatosis,  and  an  occasional  myelocyte 
in  three  other  cases. 

Bibliography. 

Cancer,  Sarcoma. 

Alexander.     These  de  Paris,  1887. 

AndraL     Archiv  gen.  de  Med.,  June,  1823. 

Bierfreund.     Langenbeck's  Archiv,  Bd.  41,  p.  1. 

Biernachi.     Zeit.  f.  physiol.  Chem.,  Bd.  19. 

Braun.     Wien.  med.  Woch.,  1896,  pp.  482,  582. 

Baland.     Fort.  d.  Med.,  1891,  No.  20. 

Behio.     St.  Petersb.  med.  Woch.,  1891,  p.  1. 

Bevoto.     Zeit.  f.  Heilk.,  1891,  p.  176. 

Dieballa.     Deut.  Archiv  klin.  Med.,  Bd.  57,  p.  302. 

Ehrlich.     Charit^-Annalen,  1878,  Bd.  5. 

Eichhorst.     Spec.  Path.  u.  Therap.,  Bd.  II. 

Eisenlohr.     Deut.  Archiv  klin.  Med.,  Bd.  20,  p.  495. 

Epstein.     Wien.  med.  Presse,  1894,  p.  2050. 

Escherieh.     Berl.  klin.  Woch.,  1884,  p.  145. 

Fede.     Cited  by  Ehrlich,  Charit^-Annalen,  Bd.  5. 

Fleischer,  Penzoldt.     Deut.  Archiv  klin.  Med.,  Bd.  26,  p.  368. 

Freund.     Cong.  f.  inn.  Med.,  1889. 

Grawitz.     2  Virchow's  Archiv,  1876,  p.  323. 

Haherlin.     Miinch.  med.  Woch.,  1888,  No.  22. 

Hammarschlag.     Zeit.  f.  klin.  Med.,  Bd.  21. 

Hampeln.     Cited  by  Neubert. 

Haussler.     Diss.  Greifswald,  cited  by  Muller. 

Herter.     Trans.  N.  Y.  Path.  Soc,  1900. 

V.  Jaksch.  » Wien.  med.  Woch.,  1883,  pp.  473,  512.  ^Zeit.  f.  klin.  Med.,  Bd.  6,  p. 
423. 

Klemperer.     Charit^-Annalen,  Bd.  15,  1890. 

Laache.     Die  Anemie,  1883. 

Laker.     Wien.  med.  Woch.,  1886,  Nos.  18-20. 

Lebert.     Krankh.  d.  Magens.  Tubingen,  1877,  p.  481. 

Leichtenstern.  lUnters.  u.  d.  Hb-gehalt.,  etc.,  Leipsic,  1878.  ^Ziemsenn's  Handb., 
Bd.  8,  p.  344. 

Martin,  Matthewson.     Brit.  Med.  Jour.,  Dec.  5,  1896. 

Matrai.     Pest.  med.  chir.  Presse,  1885. 

Mayer.     Aerzt.  Intelligensbl.,  1870,  No.  21. 

Moraczewsky.     Virchow's  Archiv,  Bd.  114,  p.  127. 

Mosler.     Virchow's  Archiv,  Bd.  114,  p.  461. 

Mosler,  Gast.     Deut.  med.  Woch.,  1885. 

Mouisset.     Eevue  de  Med.,  1891,  p.  885. 

F.  Muller.     Zeit.  f.  klin.  Med.,  Bd.  16. 

Neubert.     Inaug.  Diss.  Dorpat,  1899.     St.  Petersb.  med.  Woch.,  1889,  No.  32. 

V.  Noorden.     Lehrb.  d.  Path.  d.  Stoffwechsels.,  p.  461. 

Osterspey.     Berl.  klin.  Woch.,  1892,  pp.  271,  308. 

Palma.     Deut.  med.  Woch.,  1892,  p.  784. 

Patrigeon.     These  de  Paris,  1877. 

Peiper.     ^Cent.  f.  klin.  Med.,  1891,  p.  217.     « Virchow's  Archiv,   Bd.  116,  p.  337. 

Potain.     Gaz.  d.  Hop.,  1888,  p.  525. 

Beinbach.     Langenbeck's  Archiv,  Bd.  46,  p.  486. 

Bumpf.     Cent.  f.  klin.  Med.,  1891,  p.  441. 

Sadler.     Fort.  d.  Med.,  1892;  Suppl.  Sept.,  p.  38. 

Sailer,  Taylor.     Internat.  Med.  Mag.,  Vol.  6,  p.  404. 


376  MALIGNANT  TUMORS. 

SchmaUz.     Deut.  Archiv  klin.  Med.,  Bd.  47,  p.  145. 

Scholkoff.     Diss.  Bern,  1892. 

Senator.     Berl.  klin.  Woch.,  1882,  No   19. 

Stintzing,  Gumprecht.     Deut.  Archiv  klin.  Med.,  Bd. 

Strauer.     Inaug.  Diss.  Greifswald,  1893. 

Strauss.     Charit^-Annalen,  1899. 

TrinkUr.     Cent.  f.  med.  Wissen.,  1890. 

Welch.     Pepper's  Syst.  Med.,  Vol.  2,  p.  552. 

Westphal.     Diss.  Greifswald,  1887. 


53,  p.  265. 


PART  VI. 
ANIMAL  PARASITES. 

CHAPTER    XXIII. 
MALARIA. 

I.     TECHNICS. 

(a)  The  Examination  of  Fresh  Blood. — By  far  the  readiest  method 
of  determining  the  presence  of  malarial  infection  is  by  the  examination 
of  the  fresh  blood.  For  this  purpose  thoroughly  cleaned  and  polished 
slides  and  cover-glasses  are  the  chief  requisites,  and  a  thin  layer  of 
blood  may  be  secured  by  touching  the  exuded  drop  to  the  cover-glass, 
which  is  immediately  laid  upon  the  slide  and  examined  with  a  one- 
twelfth  immersion  lens.  The  quantity  of  blood  should  be  small,  and 
in  the  resulting  layer  the  red  cells  should  be  separated  from  each 
other.  Besides  the  facility  in  preparation,  this  method  permits  the 
study  of  the  vibratory  motion  of  pigment,  of  ameboid  motion  of  the 
parasite,  of  some  limited  phases  of  the  natural  development  of  the 
parasite,  such  as  exflagellation,  and  of  some  artificial  changes,  such  as 
the  escape  of  the  parasite  from  the  cell,  and  occasionally  of  the  forma- 
tion of  vacuoles. 

By  mixing  the  blood  with  ascitic  fluid  deeply  tinged  with  methylene- 
blue,  Celli  and  Guarnieri  secured  excellent  stained  specimens  of  the 
parasite  in  the  fresh  condition.  The  ascitic  fluid  was  prepared  by  dis- 
solving powdered  methylene-blue  in  the  fluid  and  filtering.  The  blood 
was  mixed  with  this  fluid  and  spread  under  a  cover-glass  in  the  usual 
way.  Their  drawings  of  parasites  seen  under  these  conditions  appear 
to  have  been  the  first  definite  representation  of  the  nuclear  body  of 
the  malarial  organism.  No  other  notable  modification  of  the  method 
of  examining  malarial  blood  in  the  fresh  condition  appears  to  have 
been  perfected. 

Concerning  the  value  and  reliability  of  these  methods  opinions  are 
somewhat  at  variance.  Most  of  the  early  study  of  malarial  blood  was 
made  exclusively  by  this  method,  and  it  still  remains,  of  course,  the 
only  method  permitting  the  minute  study  of  many  important  changes 
in  the  form  of  the  parasite,  of  the  motility  of  the  pigment  and  of  some 
degenerative  processes.  On  the  other  hand,  exclusive  reliance  on  this 
method  appears  to  have  been  responsible  for  much  confusion  regarding 
the  varieties   of  the  parasite,  and  its  minute  structure,  as  well   as  for 


378  MALARIA. 

many  erroneous  interpretations  of  exceptional  or  artificial  changes  in 
the  organism. 

As  a  ready  means  of  diagnosis,  in  the  hands  of  an  expert,  the  ex- 
amination of  fresh  blood  is  all  that  is  required  in  the  average  case,  and 
when  the  parasites  are  moderately  numerous  and  when  crescents  are 
present,  even  an  inexperienced  observer  can  hardly  err.  Under  any 
other  conditions,  except  for  special  purposes,  reliance  upon  this  method 
appears  to  the  writer  inadvisable.  When  the  parasites  are  scarce, 
especially  when  they  are  of  the  small  unpigmented  form,  a  prolonged 
search  through  fresh  blood  has  frequently  proven  negative,  in  the 
writer's  experience,  although  a  few  minutes  sufficed  for  the  discovery 
of  one  or  more  minute  parasites  in  the  stained  specimen.  Practically, 
this  fact  demands  that  a  negative  result  with  a  fresh  specimen  be  in- 
variably controlled  by  the  examination,  with  mechanical  stage,  of  a 
stained  specimen.  Moreover,  any  one  who  is  familiar  with  the  host  of 
appearances  in  fresh  blood  simulating  the  malarial  parasite  must  regard 
with  some  suspicion  the  report,  from  anyone  but  a  recognized  expert, 
of  the  discovery  of  one  or  two  "  hyaline  bodies."  From  these  consid- 
erations the  writer  would  limit  the  use  of  fresh  specimens  to  the  study 
of  a  few  special  features  of  malarial  parasites,  and  would  urgently  rec- 
ommend that  as  a  diagnostic  procedure  reliance  be  placed  only  upon 
the  examination  of  dry  specimens  stained,  preferably,  by  Nocht's 
method. 

The  study  of  flagellate  bodies  may  be  conducted  in  fresh  specimens 
prepared  in  the  ordinary  way,  but  placed,  if  possible,  on  a  warm  stage. 
Mannaberg:  alone  claims  to  have  found  the  flaorellate  bodies  in  consid- 
erable  numbers  in  the  fresh  human  blood  immediately  after  shedding. 
Usually  they  appear  only  after  the  lapse  of  10-20  minutes,  when  they 
may  form  in  variable  numbers  from  the  larger  tertian  or  crescentic 
estivo-autumnal  organisms,  less  frequently  from  quartan  parasites. 

The  addition  of  a  little  water  or  salt  solution  may  facilitate  the  es- 
cape of  the  parasite  from  the  red  cell  and  the  formation  of  flagella. 

The  successful  action  of  moisture  has  been  obtained  by  several  ex- 
pedients. Marshall  added  about  an  equal  quantity  of  water  to  a  small 
drop  of  blood  containing  many  crescents  and  saw  the  almost  immediate 
change  of  crescents  to  spheroidal  bodies,  followed  by  exflagellation. 
Manson  recommends  that  the  blood  under  the  cover-glass  be  kept 
moist  by  exposure  to  steam  exhaled  from  a  hot  moist  sponge.  After  a 
few  minutes  the  cover  may  be  carefully  removed,  the  specimen  dried, 
and  the  flagellate  bodies  stained. 

The  writer  finds  that  the  moist  chamber  may  be  secured  in  a  Petri 
dish  with  tightly  fitting  vaselined  cover.  Wet  blotting  paper  placed 
in  the  dish  furnishes  the  necessary  moisture.  Specimens  spread  on 
slides  or  covers  may  be  kept  moist  for  10-20  minutes  in  such  dishes, 
and  flagellation  proceeds  with  moderate  rapidity. 

A  simple  method  is  as  follows  :  Cut  an  opening  |  x  1  inch  in  a  piece 
of  thick  blotting  paper  and  moisten  the  paper  in  hot  water.  Spread 
two  glass  slides  rather  thickly  with  fresh  blood,  lay  the  blotting  paper 


STAINING  METHODS.  379 

ou  one  slide,  cover  the  cut  opening  by  the  other,  specimen  side  down, 
and  slip  a  rubber  band  about  both.  After  15—20  minutes  the  slides 
and  paper  may  be  separated  and  the  two  specimens  dried. 

(b)  Preparation  of  Dry  Specimens. — Smears  of  the  blood  may  be 
prepared  by  any  of  the  usual  methods.  After  drying  thoroughly  in 
the  air,  the  malarial  parasite  stains  best  after  fixation  in  95-97-per- 
cent alcohol  for  15—30  minutes.  Five  minutes  fixation  will  suffice, 
but  if  left  in  alcohol  over  night  the  staining  qualities  of  the  organism 
will  sometimes  be  found  slightly  altered.  When  slides  have  been 
kept  in  alcohol,  or  in  the  air,  after  fixation  by  heat  or  alcohol,  for 
periods  varying  from  one  month  to  three  years,  there  is  a  progressive 
loss  of  the  capacity  to  unite  with  eosin,  while  methylene-blue  gives  a 
deep  diffuse  stain.  This  tendency  may  be  gradually  corrected  by 
passing  the  slides  rapidly  through  a  one-tenth-percent  solution  of 
nitric  acid. 

Fixation  by  heat  is  less  satisfactory  for  the  present  purpose,  and  the 
addition  of  ether  to  the  alcohol  secures  no  advantage. 

In  a  critical  study  of  the  malarial  parasite  full  reliance  cannot  be 
placed  on  specimens  that  have  been  fixed  longer  than  a  few  weeks,  after 
which  period  there  are  often  distinct  alterations  in  the  staining  charac- 
ters of  the  organism. 

Staining  Methods.  Eosin  and  Methylene -Blue. — For  ordinary 
purposes,  staining  by  eosin  and  methylene-blue  may  be  generally  recom- 
mended, and  many  of  the  detailed  studies  of  the  parasite  have  been 
based  upon  specimens  stained  in  this  way.  The  solutions  required 
are  :  (1)  a  saturated  alcoholic  solution  of  Ehrlich's  blood  eosin,  diluted 
with  an  equal  quantity  of  95-percent  alcohol,  and  (2)  a  saturated  watery 
solution  of  Ehrlich's  rectified  methylene-blue,  at  least  one  week  old. 

A  light  staining  by  eosin,  such  as  is  given  by  the  diluted  solution 
of  eosin,  is  essential  for  the  clear  demonstration  of  the  parasite  by 
methylene-blue,  and  in  specimens  containing  only  the  small  signet- 
ring  forms,  heavy  staining  by  eosin  may  almost  entirely  prevent  the 
subsequent  action  of  methylene-blue,  and  these  minute  parasites  may 
be  overlooked. 

By  intense  staining  with  old  solutions  of  alcoholic  eosin  which  have 
absorbed  water,  fragments  of  the  red  cell  probably  containing  traces 
of  Hb  may  often  be  demonstrated  in  the  meshes  of  the  parasite,  of 
the  presence  of  which  no  indication  is  given  by  the  usual  method. 

Methylene-blue  fails  to  stain  the  young  ring  forms,  especially  of  the 
tertian  type,  as  clearly  as  is  desirable,  and  more  powerful  basic  stain- 
ing fluids  may  well  be  employed  for  this  purpose.  Nocht's  method 
may  be  recommended  over  any  other,  as  it  facilitates  the  identification 
of  the  sniall  rings  by  means  of  a  large  densely  stained  nucleus,  but 
when  this  method  cannot  be  employed,  one  may  resort  to  the  method 
modified  by  Futcher  and  Lazear  from  the  suggestions  of  Benario  and 
of  Marchoux,  as  follows  : 

"Fix  the  specimens  5  minutes  in  95-percent  alcohol,  to  100  cc.  of 
which  have  been  added  1  cc.  of  formalin.     Stain   1—3  minutes  in  the 


380  MALARIA. 

following  mixture  :  Saturated  alcohol  solution  thionin,  20  cc;  20-per- 
cent carbolic  acid,  100  cc.  The  fixing  solution  must  be  used  fresh, 
and  the  staining  fluid  must  be  at  least  one  week  old.  The  rings  are 
then  densely  stained  and  the  specimens  do  not  fade." 

The  sharpest  demonstrations  of  minute  ring-shaped  parasites  secured 
by  the  writer  were  obtained  by  staining  one  hour  in  diluted  Gage's 
hematoxylon  before  treatment  by  eosin  and  methylene-blue.  Hema- 
toxylon  stains  the  nucleus  of  the  ring  and  makes  the  body  of  the  para- 
site blacker  after  methylene-blue.  Such  specimens  are  specially  suit- 
able for  photography. 

The  Nocht-Romanowsky  Method. — The  method  originally  devised  by 
Romanowsky,  and  which  has  given  such  uncertain  results  in  the  hands 
of  many  investigators,  has  now  been  modified  most  successfully  by 
Nocht,  whose  procedure  gives  positive  results  without  much  dependence 
upon  the  quality  of  dyes  or  the  time  of  staining.  (The  interesting 
history  of  this  stain  may  be  found  in  the  writer's  article  on  Malarial 
Parasitology,  Journal  of  Experimental  Medicine,  1901.) 

Nocht's  modification  consists  in  the  addition  of  a  few  drops  of 
neutralized  Unna's  polychrome  methylene-blue  (Griibler)  to  the  1-per- 
cent solution  of  ordinary  methylene-blue.  The  usual  specimen  of  poly- 
chrome methylene-blue  is  distinctly  alkaline,  and  to  be  rendered  effectual 
for  the  present  purpose  Nocht  found  that  it  requires  neutralization, 
preferably  by  acetic  acid.  This  may  be  done  by  adding  drop  by  drop 
of  dilute  2-3-percent  acetic  acid  till  the  commercial  fluid  polychrome 
blue  no  longer  turns  red  litmus  blue  above  the  zone  coming  into  im- 
mediate contact  with  the  dye.  The  writer  has  never  failed  to  secure 
a  good  result  by  the  following  procedure  : 

1.  To  1  ounce  of  polychrome  methylene-blue  (Griibler)  add  5  drops 
of  3-percent  solution  of  acetic  acid  (U.  S.  P.,  33  percent). 

2.  Make  a  saturated  1 -percent  watery  solution  of  methylene  blue, 
preferably  Ehrlich's  (Griibler)  or  Koch's,  dissolving  the  dye  by  gentle 
heat.  This  solution  improves  with  age,  and  should  be  at  least  one 
week  old. 

3.  Make  a  1 -percent  watery  solution  of  Griibler's  watery  eosin. 
The  mixture  is  prepared  as  follows  : 

To  10  cc.  of  water  add  four  drops  of  the  eosin  solution,  6  drops 
of  neutralized  polychrome-blue,  and  2  drops  of  1 -percent  methylene- 
blue,  mixing  well.  The  specimens,  fixed  in  alcohol,  or  by  heat,  are 
immersed,  specimen  side  down,  for  1  to  2  hours,  and  will  not  overstain 
in  24  hours.  The  density  of  the  blue  stain  may  be  varied  to  suit  in- 
dividual preferences.  The  above  proportions  need  not  be  rigidly  fol- 
lowed, but  the  polychrome  solution  should  be  accurately  neutralized, 
and  the  staining  mixture  should  be  deep  blue. 

Nocht  later  reports  that  the  two  solutions  of  methylene-blue  may  be 
replaced  by  a  1-percent  solution  of  Ehrlich's  methylene-blue,  alkalin- 
ized  by  J  percent  of  NaOH  and  kept  a  few  days  in  a  thermostat 
at  50°  C.  This  is  the  ordinary  laboratory  method  of  improvising 
polychrome  methylene-blue.     To  2  cc.  of  water  add  2-3  drops  of  1- 


THE   TERTIAN  PARASITE.  381 

percent  watery  eosin,  and  drop  by  drop  of  the  alkalinized  methylene- 
blue  till  the  original  red  color  of  the  eosin  has  almost  disappeared. 
In  this  fluid  specimens  stain  in  5-10  minutes.  This  method  is  less 
reliable  than  the  former. 

The  rationale  of  the  Nocht-Romanowsky  method  is  not  yet  fully  under- 
stood, but  it  appears  most  probable  that  a  staining  agent  which  unites  selec- 
tively with  chi'omatin  exists  ready- formed  in  polychrome  methylene-blue, 
and  may  be  developed  in  specimens  of  methylene-blue  in  various  ways, 
among  which  is  slow  digestion  with  an  alkali  and  heat.  Nocht  refers  to  this 
principle  as  "  red  from  methylene-blue."  It  is  not  the  commercial  methy- 
lene-red,  but  may  be  extracted  from  polychrome  methylene-blue,  etc.,  by 
chloroform  (Nocht),  and  it  is  a  reasonable  expectation  that  it  can  be  put  on 
the  market  in  pure  form. 

Goldhorn  has  recently  succeeded  in  digesting  methylene-blue  with  satu- 
rated solution  of  lithium  carbonate  so  as  to  develop  in  it  a  large  proportion 
of  the  red  chromatin-staining  principle.  This  fluid,  neutralized  by  acetic 
acid,  not  only  stains  the  chromatin  rapidly  (15-60  seconds),  but  demonstrates, 
l)etter  than  has  yet  been  done,  early  and  extreme  granular  degeneration  of 
the  infected  and  other  red  cells.  Goldhorn's  fluid,  ready  for  use,  can  be 
obtained  from  New  York  dealers.  (See  Trans.  N.  Y.  Path.  Soc,  February, 
1901.) 

Nocht's  method  furnishes  so  much  information  regarding  the  minute 
structure  of  the  parasite,  and  renders  its  identification  so  complete  and 
positive,  that  it  must  be  recommended  above  all  other  methods  of 
staining  the  malarial  parasite.  Moreover,  it  has  a  large  field  of  ap- 
plication in  the  study  of  nuclear  structures  in  various  other  micro- 
organisms. 

II.  MORPHOLOGY. 

The  Tertian  Parasite. 

1.  The  youngest  form  of  the  tertian  parasite  seen  in  the  red  cell  is 
identical  in  appearance  with  the  spore  of  the  parent  rosette.  It  is  a 
compact  spheroidal  or  slightly  oval,  or  irregular  body,  about  2  //  in 
diameter.  It  shows  an  outer  rim  of  basophilic  protoplasm  inclosing  a 
single  large  nuclear  body  which  is  achromatic  to  methylene-blue  but 
stains  readily  in  hematoxylon  or  by  Nocht's  method,  and  which  is  usu- 
ally inclosed  or  accompanied  by  a  clear  achromatic  substance,  termed 
by  Gautier  "  the  milky  zone."     (Plate  XI.,  Fig.  1.) 

In  the  fresh  condition  these  bodies  are  noticeably  refractive,  espe- 
cially the  nucleus,  change  their  position  but  rarely  their  shape,  and  are 
never  pigmented.  From  the  earliest  period  of  infection  the  red  cell  is 
often  swollen. 

2.  The  Young  Tertian  Ring. — Within  a  few  hours  after  the  chill  the 
parasite  is  usually  found  to  have  assumed  a  somewhat  characteristic 
ring  shape  which  it  commonly  maintains  in  some  definite  form  up  to 
the  pre-segmenting  stage. 

These  bodies  measure  from  3-4 /i  in  diameter,  and  the  regular  ring 
form  is  retained  without  marked  increase  in  bulk  at  any  point,  for  6-8 
hours.     Sometimes  the  ring  is  elongated,  one  arm  reaching  across  the 


382  MALABIA. 

cell,  while  a  thin  bow  persists.  Occasionally  the  ring  appears  to  un- 
fold, and  the  parasite  stretches  clear  across  the  swollen  cell,  with  the 
nucleus  at  one  end.  The  tertian  ring  is  rarely  as  geometrical  or  deli- 
cate as  the  estivo-autumnal  signet-ring.  The  development  of  pigment 
is  inconstant,  some  large  rings  failing  to  show  pigment,  but  usually 
one  or  more  fine  grains  are  to  be  seen  in  the  medium-sized  and  smaller 
forms.  The  ring  always  encloses  a  considerable  mass  of  hemoglobin. 
The  nuclear  body  of  the  tertian  ring  is  its  most  characteristic  feature, 
appearing  as  a  rather  large,  achromatic,  highly  refractive  body,  after 
methylene-blue,  but  staining  intensely  with  hematoxylon  and  by 
Nocht's  method. 

Significance  of  the  Ring  Form. — In  regard  to  the  formation  and  signifi- 
cance of  the  ring  opinions  are  at  variance.  Most  of  the  Italian  writers  hold 
that  the  ring  form  is  not  really  a  ring,  being  bridged  across  by  a  transparent 
and  vesicular  nucleus.  There  are  many  considerations  favoring  this  view, 
especially  the  usual  appearance  of  the  parasite  in  the  fresh  condition,  and 
the  fact  that  the  chromatin  usually  lies  within  the  ring,  eventually  filling  it. 
On  the  other  hand,  Mannaberg  and  Ziemauu  claim  that  this  body  is  a  true 
ring,  formed  by  the  thinning  of  the  central  portion  of  the  body  of  the  para- 
site, and  state  they  have  seen  the  ring  develop  in  this  manner  in  the  fresh 
blood.  From  the  examination  of  the  rings  themselves  the  writer  has  been 
unable  to  convince  himself  as  to  which  view  is  correct,  but  there  are  some 
early  forms  of  the  parasite  which  strongly  indicate  that  the  ring  does  not 
represent  a  vesicular  nucleus.  In  one  such  form  the  ring  isunfolded  and  the 
nuclear  body  of  the  parasite  lies  naked  in  the  hemoglobin.  Moreover,  elon- 
gated forms  of  the  young  parasite  are  often  seen  in  which  the  ring  is  absent 
and  the  nuclear  body  lies  bare  at  one  end.  These  forms  vividly  recall  the 
appearance  of  the  ameba  dysenterise  in  which  the  nucleus  remains  at  the 
hinder  end  during  active  movements  of  progression.  Further,  it  is  difficult 
to  associate  the  relatively  huge  size  of  the  ring  with  any  nuclear  structure, 
which  would  require  the  young  malarial  parasite  to  have  a  nucleus  which  is 
larger  than  that  of  the  adwlt  cuneba  dysenterix.  Again,  secondary  rings  some- 
times form  from  the  union  of  pseudopodia,  and  these  are  identical  iu  appear- 
ance with  the  primary  ring,  but  lack  the  chromatin  granules. 

In  specimens  stained  by  Nocht's  method  the  chromatin  is  usually  found 
within  the  ring,  sometimes  lying  in  an  isolated  position  in  the  center,  but 
very  often  the  chromatin  is  found  outside  of  the  ring,  connected  by  a  very 
fine  thread  of  protoplasm.  If  the  ring  represents  a  vesicular  nucleus,  we 
have  here  the  anomaly  of  a  complete  separation  of  chromatin  from  the 
vesicular  portion  of  the  nucleus,  which  is  opposed  to  some  rigid  histological 
principles.  Even  more  frequently  the  chromatin  is  found  to  be  inclosed  by 
bluish  staining  protoplasm  which  shuts  it  off"  entirely  from  the  ring.  (Plate 
XL,  Fig.  7.) 

From  various  biological  studies  it  appears  that  the  nuclei  of  the  protozoa 
are  usually  widely  different  from  the  nuclei  of  metazoa.  Many  protozoa  do 
not  have  a  vesicular  nucleus,  with  cell  membrane,  linin,  nucleolus,  etc.,  but 
possesses  the  so-called  "  distributed  nucleus''''  composed  of  a  number  of  gran- 
ules lying  free  in  the  body  of  the  parasite.  The  study  of  the  malarial  para- 
site by  Nocht's  method  indicates  that  the  nucleus  of  this  protozoan  is  of  the 
distributed  type,  which  does  not  exhibit  a  vesicular  appearance  nor  possess  a 
nuclear  membrane.  (See  Calkins  on  "Protozoan  Nuclei,"  Annals  N.  Y. 
Acad.  Sciences,  Vol.  IX.,  Part  III.,  1898.)  On  these  grounds  the  writer  is 
inclined  to  agree  with  Mannaberg  and  others  who  hold  that  the  form  in 
question  is  a  true  ring,  a  form  usually  but  not  necessarily  assumed  by  the 
parasite,  and  does  not  represent  a  vesicular  nucleus. 


PLATE   X 


Developmental    Cycle   of    Benign  Tertian   Parasite. 


Fig.  I.   Veryearly  form  of  parasite,  showing  chromatin  granule,  "milky  zone,"  and  spheroidal  body. 

Figs.     2,  3.     Typical  young  ring-shaped  parasites. 

Figs.  4,  5.     Subdivision   of  chromatin,  development    of   body,   and    appearance  of  pigment  in 

later  ring-forms. 
Fig.  6.     Double  rings,  in  single  parasite. 

Figs.  7,8.     Turban-sliaped  parasites.     Secondary  rings,  eccentric  jiosition  of  chromatin. 
Fig.  9.     Double  infection  of  cell. 

Figs.    10,  II.     Complex  ameboid  figures  in  doubly  infected  cells. 
Fig.   12.     Full  grown  form,  with  large  eccentric  nucleus. 

Figs.  13,  14.  Protrusion  of  chromatin  granules  and  milky  substance  in  body  of  full  grown  parasite. 
Figs.  15,  16.  Division  of  chromatin  granules  into  groups  in  reticulated  presegmenting  bodies. 
Fig.   17.     Tertian  rosette. 


THE  TERTIAN  PARASITE.  383 

Marchiafava  and  Bignami  still  hold  that  the  ring  is  bridged  over  by  an 
invisible  membrane.  They  do  not  insist,  as  do  many,  that  this  membrane 
is  a  nuclear  structure,  but  consider  the  central  area  to  be  a  digestive  vacuole. 

Comparison  of  the  Tertian  and  Estivo-autumnal  Rings. — From  the 
study  of  the  ring-shaped  tertian  parasite  and  the  estivo-autumnal  sig- 
net-ring forms,  in  typical  cases  of  these  infections,  the  writer  believes 
that  these  parasites,  with  very  rare  exceptions,  can  be  fully  distin- 
guished from  each  other  in  this  early  stage,  and  on  the  following  pe- 
culiarities : 

1.  The  nuclear  body  and  chromatin  mass  of  the  young  tertian  para- 
site is  achromatic  to  methylene-blue,  which  densely  stains  the  nucleus 
of  the  estivo-autumnal  organism.  The  writer  has  been  unable  to  find 
in  the  literature  any  specific  reference  to  this  diagnostic  peculiarity, 
which  may  be  readily  verified  by  comparing  specimens  of  the  two 
parasites  stained  by  methylene-blue  and  by  Nocht's  method.  (The 
dense  staining  of  a  nuclear  body  in  the  young  estivo-autumnal  para- 
site has  often  been  noted,  and  in  1894  Okintschitz  mentioned  the  fact 
that  the  nucleus  of  the  young  tertian  parasite  fails  to  stain  by  methy- 
lene-blue.) 

2.  The  shape  and  contour  of  the  tertian  ring  is  usually  coarse  and 
irregular,  but  the  estivo-autumnal  ring  is  geometrically  circular,  more 
delicate,  with  an  extremely  fine  bow,  and  usually  with  a  typical  signet- 
like swelling.     (Cf.  Plate  XI.,  Figs.  2,  3,  and  Plate  XIII.,  Figs.  6,  7.) 

3.  One  or  two  grains  of  pigment  are  almost  invariably  found  in  the 
early  tertian  ring,  but  are,  with  nearly  equal  constancy,  absent  from 
the  estivo-autumnal  signet  ring. 

4.  The  writer's  specimens  confirm  the  statement  of  Gautier  that  the 
tertian  ring  is  usually  pigmented  before  the  chromatin  becomes  subdi- 
vided, while  the  chromatin  of  the  estivo-autumnal  ring  is  always  sub- 
divided before  the  appearance  of  pigment.  In  some  cases,  however, 
the  chromatin  of  the  tertian  ring  divides  before  pigmentation. 

5.  The  infected  cell  is  usually  swollen  from  the  moment  of  infection 
by  the  tertian  spore,  and  commonly  shrunken  w4ien  harboring  the 
estivo-autumnal  ring. 

All  of  these  characters  are  usually  apparent  in  ordinary  specimens, 
but  naturally  are  most  distinct  in  flatly  spread  and  rapidly  dried  cells. 
The  writer  has  met  with  no  exception  to  the  above  rules  in  cases  infected 
by  the  tertian  parasite  in  New  York  and  cases  of  estivo-autumnal  infec- 
tion from  Cuba.  In  many  of  the  irregular  relapses,  in  cases  showing 
tertian  organisms,  encountered  among  volunteer  soldiers  long  returned 
from  Cuba  single  ring-shaped  parasites  not  admitting  of  positive  iden- 
tification have  sometimes  been  seen.  The  significance  of  this  observa- 
tion will  be  considered  later.  (See  section  on  Plurality  of  Species  among 
malarial  parasites.) 

3,  Large  Tertian  Rings. — After  a  period  of  6-8  hours,  the  tertian 
ring  is  usually  found  to  have  developed  an  outgrowth  which  is  actively 
ameboid  in  the  fresh  condition  and  appears  in  stained  specimens  as  a 
tongue-like  protrusion  or  turban-shaped  mass  attached   to    one  seg- 


384  MALARIA. 

ment  of  the  ring.  (See  Plate  XI.)  The  nuclear  body  meanwhile 
increases  slightly  in  size,  projecting  into  the  ring,  and  the  chromatin 
divides  into  several  large  granules. 

At  this  period  occurs  the  greatest  ameboid  activity  of  the  parasite 
and  in  some  severe  tertian  infections  the  organism  may  be  found  fixed 
in  the  height  of  its  ameboid  excursions,  when  it  presents  in  stained 
specimens  the  peculiar  appearance  depicted  in  Plate  XI.,  Figs.  9,  10. 
There  the  ring  persists  but  the  body  of  the  parasite  is  strung  out 
into  a  number  of  slender  threads  with  nodal  thickenings.  At  times, 
especially  in  cases  taking  quinine,  the  number  and  delicacy  of  the 
threads  greatly  exceeds  those  seen  in  the  sketch,  which  represents  an 
average  instance. 

A  close  inspection  of  cells  harboring  such  parasites  may  disclose  the 
presence  in  one  cell  of  two  distinct  nuclear  bodies,  indicating  the  co- 
existence of  two  parasites.  Frequently  twin  parasites  entirely  separate 
from  the  other  are  found  in  the  same  cell,  each  of  which  shows  a  ten- 
dency to  develop  the  long  threads.  (See  Plate  XI.,  Fig.  9.)  When, 
however,  the  threads  are  numerous  and  very  thin,  it  is  usually  impos- 
sible to  find  any  break  in  their  continuity,  while  in  many  instances  the 
two  parasites  are  distinctly  united.  The  significance  of  these  forms 
will  be  considered  later.      (^See  Conjugation,) 

4.  Tertian  Spheroidal  Bodies. — During  the  second  quarter  of  the  cycle, 
the  body  and  the  nucleus  of  the  parasite  develop  rapidly  in  size, 
ameboid  motion  and  ameboid  figures  gradually  diminish,  and  pigment 
is  abundantly  deposited  in  the  form  of  fine  dark  brown  or  yellowish 
grains  showing  in  the  fresh  state  active  vibratory  motion.  The  in- 
fected cell  continues  to  increase  slightly  in  size,  and  its  hemoglobin  is 
progressively  diminished. 

Depending  upon  the  character  of  ameboid  activity  the  variety  of 
figures  seen  during  this  period  is  very  great.  Eventually,  toward  the 
end  of  24  hours  or  possibly  somewhat  later,  the  parasite  occupies 
three-fourths  of  the  swollen  cell,  in  the  form  of  a  spheroidal  or  ellip- 
tical, homogeneous  body,  the  outer  portion  of  which  contains  most  of 
the  pigment  and  is  rather  more  deeply  stainable  than  the  zone  imme- 
diately surrounding  the  nucleus.  (Plate  XI.,  Fig.  12.)  The  nucleus 
gradually  increases  in  size,  growing  into  the  ring.  It  no  longer  has 
the  appearance  of  a  small  highly  refractive  achromatic  spot  (after 
methylene-blue)  but  takes  a  light  bluish  tinge  with  1-percent  methy- 
lene-blue,  and  stains  less  deeply  than  before  with  hematoxylon.  At 
the  end  of  this  period  the  nucleus  completely  fills  the  ring,  stains 
rather  distinctly  with  methylene-blue  and  sometimes  exhibits  a  deli- 
cate bluish  network. 

After  Nocht's  method  the  changes  in  the  nucleus  are  found  to  consist  in 
the  gradual  subdivision  of  the  chromatin  granules,  which  finally  become 
rather  numerous,  of  minute  size,  and  more  difficult  to  stain. 

Usually  these  chromatin  granules  lie  on  the  inner  circumference  of  the 
bow  of  the  ring,  projecting  within  the  ring,  and  partly  surrounded  by  a 
"  milky  "  unstained  zone.     This  milky  zone  is  often  absent  in  young  para- 


THE  TERTIAN  PARASITE.  385 

sites  in  cells  thinly  spread  and  rapidly  dried,  but  in  older  parasites  it  is  al- 
ways present.  Various  other  positions  may  be  assumed  by  the  chromatin 
mass,  as  follows  : 

A  subdivision  of  the  granules  into  two  distinct  groups,  separated  by  a 
strand  of  bluish  stained  protoplasm  ;  an  excentric  position  entirely  apart 
from  the  ring  ;  a  position  midway  between  two  rings  found  in  the  same  par- 
asite ;  a  position  in  the  center  of  the  ring  entirely  apart  from  any  bluish 
protoplasm  ;  a  circular  arrangement  about  the  periphery  of  the  ring.  Some- 
times the  smaller  granules  are  grouped  about  a  central  larger  granule,  as 
has  been  noted  in  other  protozoa  whose  nuclei  are  of  the  intermediate 
type.     (Microglena.     Euglena.)     (Plates  XI.,  XIII.) 

5.  Full  Grown  Tertian  Parasites. — The  third  quarter  is  occupied  bj 
the  continued  growth  of  the  parasite  in  the  form  of  a  large  homogene- 
ous richly  pigmented  body  which  finally  occupies  at  least  four-fifths 
of  the  swollen  cell,  and  by  certain  nuclear  changes  which  it  is  diffi- 
cult to  follow  in  specimens  stained  by  methylene-blue  or  hematoxy- 
lon,  but  are  fully  demonstrated  by  Nocht's  method.  The  exact  limits 
within  which  the  parasite  may  be  termed  "  full  grown  "  can  be  sharply 
fixed  only  with  great  difficulty,  but  there  appears  to  be  a  period  of  at 
least  twelve  hours,  during  which  there  is  little  change  in  the  structure 
of  the  organism  and  during  which  the  body  stains  homogeneously  and 
the  nucleus  occupies  the  entire  ring.  The  writer  would  place  this 
period  between  the  24th  and  40th  hour  of  the  cycle.  A  portion  of 
the  period  is  occupied  by  nuclear  changes  belonging  to  the  reproduc- 
tive phase  of  the  parasite's  development. 

After  the  appearance  of  a  faint  intranuclear  network  most  authori- 
ties agree  that  the  nucleus  largely  disappears  in  specimens  stained  by 
methylene-blue  or  hematoxylon,  and  is  next  seen  in  the  form  of  highly 
refractive  achromatic  spots  in  the  meshes  of  the  reticulated  pre-seg- 
menting  body  (methylene-blue),  and  these  again  stain  deeply  with  hem- 
atoxylon. 

Nocht's  method,  however,  fully  demonstrates  the  nuclear  changes  which 
occur  in  the  full-grown  parasite.  A  considerable  area,  usually  the  entire 
original  ring,  is  now  occupied  by  a  "  milky  "  or  slightly  bluish  staining  sub- 
stance, in  which  lie  a  considerable  number  of  very  fine  chromatin  granules. 
These  granules  are  usually  difficult  to  stain,  and  being  of  very  minute  size 
they  are  difficult  to  see.  This  fact  has  led  Ziemann  and  Gautier  to  admit 
the  possibility  that  the  chromatin  may  actually  disappear  at  one  stage  of  the 
development,  especially  since  they  have  found  some  large  parasites  in  which 
no  chromatin  was  demonstrable.  In  the  writer's  specimens  there  were  a 
very  few  large  tertian  parasites  in  which  no  chromatin  granules  appeared, 
but  these  were  not  more  numerous  than  younger  forms  which  were  devoid 
of  chromatin  and  which  must  therefore  be  regarded  as  sterile.  Similarly, 
the  larger  forms  devoid  of  chromatin  the  writer  would  class  with  the  sterile 
forms  rather  than  accept  the  view  that  the  chromatin  may  entirely  disappear 
at  one  stage  of  the  fertile  parasite,  a  view  which  is  at  variance  with  biological 
principles.  After  the  subdivision  of  the  chromatin  has  reached  a  limit  the 
next  change,  observed  in  a  considerable  number  of  parasites,  appears  to  con- 
sist in  the  extrusion  of  a  portion  of  the  milky  substance  and  its  chromatin 
granules  into  the  body  of  the  parasite.  (Plate  XI. ,  Fig.  13.)  At  the  same  time 
the  granules  of  chromatin  increase  in  size  and  diminish  in  number.  Other 
forms  may  be  seen  in  which  the  ' '  milky  substance  ' '  and  chromatin  granules 
occupy  an  elongated  space  within  the  body  of  the  parasite,  and  in  such 
25 


386  MALARIA. 

cases  the  beginning  concentration  of  pigment  and  deeper  stain  of  the  para- 
site indicate  the  presence  of  the  pre-segmental  stage.     (Plate  XI.,  Fig.  14.) 

6.  Pre-segmenting  bodies  usually  begin  to  appear  in  the  blood  8-10 
hours  before  the  chill. 

In  specimens  stained  by  methylene-blue  the  first  demonstrable  indi- 
cations of  the  division  of  the  parasite  are  seen  in  a  deeper  staining 
capacity  and  tendency  toward  reticulation  which  appear  throughout  the 
whole  or  in  a  part  of  the  body  of  the  parasite.  Occasionally  these 
changes  may  be  noted  in  one  half  the  parasite,  while  the  other  half 
retains  the  homogeneous  appearance  of  the  "  full  grown "  organism. 
Usually  the  process  is  found  to  have  affected  the  entire  organism,  giv- 
ing the  very  characteristic  forms  sketched  in  Plate  XI.,  Figs.  1 5, 1 6.  In 
the  pre-segmenting  bodies  the  pigment  is  gathered  in  a  reduced  number 
of  coarse  grains  or  spindles  which  lie  in  the  body  of  the  parasite,  in  a 
position  determined  by  that  of  the  new  multiple  nuclei. 

These  bodies  were  first  described  by  Golgi  in  fresh  blood  and  properly  in- 
terpreted as  belonging  to  the  process  of  segmentation.  Later  they  were  de- 
scribed by  Marchiafava  and  Celli  as  vacuolated  parasites,  the  highly  refrac- 
tive nuclear  bodies,  appearing  in  the  fresh  condition  very  much  like  vacuoles. 
Still  later,  Celli  and  Guarnieri  sketched  them  from  specimens  stained  in  the 
fresh  condition,  regarding  some  as  showing  partial  segmentation,  others  as 
vacuolated  parasites,  although  they  accurately  described  the  appearance  of 
the  nuclear  particles  invariably  found  within  these  "  vacuoles,"  while  others 
they  supposed  to  be  groups  of  confluent  parasites,  i.  e.,  true  plasmodia. 
Mannaberg's  descriptions  (1899),  referring  only  to  fresh  blood,  do  not  include 
these  bodies,  nor  have  they  found  a  distinct  place  in  his  plates,  although 
some  of  the  figures  in  Plate  IV.  indicate  that  they  have  not  escaped  his  ob- 
servation. In  Thayer  and  Hewetson's  careful  study  of  the  parasite  in  fresh 
blood,  the  pre-segmenting  bodies  are  not  described  as  such.  Laveran  (1898, 
page  62)  refers  to  the  similarity  in  appearance  between  a  nuclear  body  and 
"vacuole,"  but  he  neither  describes  nor  depicts  the  pre-segmenting  reticu- 
lated parasite.  Ziemann  describes  the  pre-segmenting  bodies  as  they  appear 
after  his  or  Romanowsky's  staining  methods,  but  the  plates  would  not  enable 
one  unfamiliar  with  the  subject  to  identify  these  forms  in  specimens  stained 
by  eosin  and  methylene-blue. 

The  reticulated  pre-segmenting  tertian  parasites  may  be  seen  in  every 
case  examined  within  6-8  hours  preceding  the  chill,  and  often  in  be- 
lated parasites  shortly  after  the  chill.  Many  transitional  stages  be- 
tween the  homogeneous  adult  parasite  and  the  perfect  rosette  may  be 
seen  in  rich  infections.  They  are  well  demonstrated  by  eosin  and 
methylene-blue,  especially  as  regards  the  increasing  density  of  stain  and 
reticulation.     After  hematoxylin  the  multiple  nuclei  stain  deeply. 

By  Nocht's  method  a  series  of  interesting  nuclear  changes  may  be  fol- 
lowed in  the  pre-segmenting  forms.  After  the  mass  of  enlarging  chromatin 
granules  and  milky  substance  has  flown  out  into  the  elongated  form  de- 
scribed above,  the  chromatin  granules  leave  the  central  clear  space  and  make 
their  way  in  groups  out  into  the  body  of  the  parasite.  Various  stages  of  this 
process  may  be  followed  in  specimens  taken  at  suitable  periods,  and  some  ob- 
served phases  are  seen  in  Plate  XI. ,  Figs.  13-15.  Considerable  differences  in 
the  number  of  such  groups  may  be  noted  in  different  cases.  Usually  a  large 
number  of  ill-defined  groups  are  seen,  before  the  central  mass  of  granules  is 


THE  TERTIAN  PARASITE.  387 

exhausted.  (Plate  XIII.,  Fig.  14.)  In  some  specimens  the  compact  nuclei  of 
the  young  spores  appear  to  form  in  one  segment  of  the  parasite  before  the 
main  mass  of  granules  has  become  exhausted.  Each  of  the  groups  appears 
always  to  be  surrounded  by  a  milky  zone,  and  the  mass  of  granules  is  often 
of  a  peculiar  triangular  form.  During  these  changes  the  pigment  granules 
increase  in  size,  diminish  in  number,  and  are  distributed  in  the  meshes  of  the 
now  distinctly  reticulated  body  of  the  parasite. 

7.  Tertian  rosettes  are  usually  seen  in  the  circulation  3  or  4  hours  be- 
fore the  chill,  most  abundantly  just  before  the  chill,  and  a  few  are 
often  to  be  found  for  one  hour  or  longer  after  the  chill. 

These  limits  may  occasionally  be  much  wider,  as  Marchiafava  and 
Celli  have  seen  rosettes  two  to  six  hours  before  the  chill  and  six  to 
seven  hours  thereafter,  and  indeed,  when  the  different  broods  of  para- 
sites are  not  very  distinct,  there  is  no  reason  why  occasional  rosettes 
should  not  be  found  at  any  period  of  the  main  cycle. 

Of  the  three  types  of  sporulation  described  by  Golgi,  the  second  type,  ac- 
cording to  which  the  entire  parasite  is  divided  into  spores  leaving  nothing 
but  pigment,  is  undoubtedly  the  usual  process.  As  regards  Golgi's  first 
type,  after  which  only  the  peripheral  portion  of  the  parasite  divides,  leaving 
a  distinct  central  globular  pigmented  body,  most  stained  specimens  fail  to 
show  convincing  evidence  that  the  physiological  segmenting  process  may  be 
subject  to  such  an  important  modification,  nor  does  it  appear  in  recent  litera- 
ture that  the  existence  of  this  variety  of  segmentation  has  been  fully  veri- 
fied. In  a  few  cases  taking  quinine,  the  writer  has  seen  rare  segmenting 
bodies  which  resembled  those  described  as  above  by  Golgi,  but  never  in  fresh 
cases.  Golgi's  third  type  of  "partial  segmentation,"  together  with  the 
lateral  circumscribed  sporulation  of  Celli  and  Guarnieri,  may  frequently  be 
seen  in  rich  tertian  infections  in  fresh  blood,  but  according  to  the  evidence 
of  stained  specimens,  must  be  classed  with  the  pre-segmeuting  forms.  The 
various  morphological  differences  seen  in  the  segmenting  forms  of  the 
separate  species  serve  to  distinguish  those  species,  but  do  not  constitute 
different  types  of  this  process. 

The  tertian  rosette  is  usually  distinguished  by  its  large  size  and 
considerable  number  of  spores,  15-20.  From  the  writer's  specimens 
it  does  not  appear,  however,  that  the  identification  of  the  tertian 
rosette  can  always  be  based  upon  the  number  of  spores,  as  these  are 
sometimes  found  to  number  under  fifteen,  though  rarely  over  twenty- 
one.  Marchiafava  and  Bignami,  however,  have  described  tertian 
rosettes  with  40—50  spores.  With  the  smaller  number  of  spores  the 
rosette  is  always  distinctly  larger  than  either  the  quartan  or  the 
estivo-autumnal  body. 

Although  rosettes  sometimes  appear  to  be  extra-cellular,  when  seen  in 
fresh  blood,  in  stained  specimens  the  writer  has  never  seen  a  clearly 
extra-cellular  segmenting  tertian  body.  Almost  invariably  there  is  an 
unbroken  ring  of  hemoglobin  about  the  parasite,  and  very  often  traces 
of  hemoglobin  may  be  found  scattered  through  amass  of  spores,  where 
they  may  be  demonstrated  by  dense  staining  with  epsin. 

The  nuclear  changes  demonstrated  by  Nocht's  method  in  the  tertian 
rosette  consist  principally  in  the  gradual  fusion  of  the  new  formed 
groups  of  chromatin  granules  into  one  compact  globule,  which  is  partly 
surrounded  by  a  '*  milky  zone." 


388  MALARIA. 

While  the  rosette  is  still  compact  the  vesicular  shape  of  the  spore  is 
distinct.  The  outer  segment  of  the  ring  is  usually  thickened,  the 
nucleus  tends  to  lie  near  the  inner  pole,  and  between  the  nucleus  and 
outer  segment  is  a  small  milky  zone. 

The  pigment  is  usually  collected  into  a  central  block  or  mass  of 
granules,  but  may  be  found  variously  scattered  among  the  spores,  or 
along  the  periphery  of  the  rosette.     (Plate  XI.,  Fig.  17.) 

The  Quartan  Parasite. 

The  earliest  form  of  the  quartan  parasite  as  seen  in  the  stained  red 
cell  is  practically  indistinguishable  from  that  of  the  tertian  organism, 
but  its  true  character  may  usually  be  suspected  from  the  slightly 
shrunken  appearance  of  the  infected  cell.  In  fresh  specimens  the 
higher  refracted  quality  of  this  body  is  often,  however,  sufficiently 
characteristic  for  its  identification.  After  a  very  slight  increase  in  size 
the  quartan  parasite  becomes  rather  easy  to  distinguish  in  both  fresh 
and  stained  specimens,  for  it  early  takes  the  form  of  a  ring,  of  the  gen- 
eral character  of  the  tertian  ring,  but  smaller,  more  compact,  and  more 
richly  and  coarsely  pigmented.  As  with  the  tertian  organism  the 
nuclear  body  is  found  projecting  into  the  ring.  In  fresh  specimens  at 
this  period,  the  higher  refractive  quality  and  slower  ameboid  motion 
are  additional  diagnostic  characters  from  the  tertian  parasite.  (Plate 
XII.) 

The  growth  of  the  quartan  ring  is  very  similar  in  all  important  re- 
spects to  that  of  the  tertian,  while  its  distinguishing  features,  especially 
the  abundance  of  coarse  pigment  grains,  are  uniformly  retained. 

During  the  pre-segmenting  stage  the  characters  of  the  quartan  para- 
site are  markedly  different  from  those  of  the  tertian.  On  account  of 
the  slower  progress  of  sporulation  and  from  the  greater  tendency  of 
the  quartan  parasite  to  complete  its  cycle  in  the  general  circulation, 
quartan  pre-segraenting  bodies  are  relatively  much  more  numerous  in 
the  stained  specimen  than  are  the  similar  forms  of  the  tertian  organism. 
In  some  specimens  taken  several  hours  before  the  chill  the  majority  of 
organisms  found  may  present  the  markedly  reticulated  structure  indic- 
ative of  approaching  division.  The  multiple  nuclei  being  less  numer- 
ous and  the  pigment  more  abundant,  the  meshes  of  the  reticulum  are 
much  coarser  and  the  pigment  is  often  found  in  irregular  partly  radi- 
ating rows.  These  coarsely  reticulated,  relatively  small,  and  richly  pig- 
mented bodies,  lying  in  markedly  shrunken  cells,  are  very  character- 
istic and  not  readily  confused  with  any  other  form  of  malarial  parasite 
commonly  found  in  the  peripheral  blood.  In  some  severe  estivo- 
autumnal  infections,  showing  many  parasites  of  all  stages  in  the 
peripheral  blood,  somewhat  similar  spheroidal  or  pre-segmenting  forms 
may  be  found  in  considerable  numbers,  but,  as  will  be  seen  by  reference 
to  Plate  XIII.,  the  character  of  the  pigment  in  the  estivo-autumnal 
parasite  is  very  different,  while  such  cases  are  very  rare,  and  readily 
recognized  on  clinical  grounds,  being  almost  invariably  of  the  perni- 
cious type. 


PLATE    XII 


Cycle   of  Quartan    Parasite. 


Fig.    I.      Very  early  non-pigmented  form. 

Figs.  2,  3,  4.     Small  quartan  rings,  with  large  chromatin  masses  and  abundance  of  pigment. 

Fig.  5.     Turban-shaped  ring,  with  subdivided  chromatin. 

Fig.  6.     Subdivision  of  ring  and  of  chromatin  granules. 

Fig.  7.     Coarse  quartan  ring  with  central  chromatin  granules. 

Fig.  8.     Full-grown  c[uartan  parasite,  with  eccentric  chromatin,  hyaline  body,  and  abundance  of 

pigment. 
Fig.  g.      Extra-cellular  reticulated  body. 
Figs.  10-13.     Quartan  presegmenting  forms. 
Fig.  14.     Quartan  rosette. 
Fig.  15.      Pigmented  mononuclear  leucocyte. 


THE  ESTIVO-AUTTJMNAL  PARASITE.  389 

The  quartan  segmenting  bodies  are  usually  more  abundant  in  the 
peripheral  circulation  than  are  rosettes  of  any  other  type,  and  are  read- 
ily identified  by  the  small  number  (6-12)  and  comparatively  large  size 
and  geometrical  arrangement  of  the  spores.    (Plate  XII.) 

The  Estivo- Autumnal  Parasite. 

The  following  description  applies  to  a  group  of  organisms,  which, 
according  to  the  Italian  school,  comprises  two  or  three  varieties  of  ma- 
larial parasites.  Waiving  for  the  present  the  question  of  a  plurality 
of  species,  the  entire  group  will  be  described  as  one,  and  the  grounds 
for  their  separation  into  two  or  more  species  v/ill  be  considered  later. 

The  earliest  form  of  the  estivo-autumnal  parasite  seen  in  the  red  cells 
is  very  similar  to  that  of  the  tertian  and  quartan  parasites,  but  is  of 
slightly  smaller  size  than  either,  and  is  often  distinguishable  from  the 
tertian  by  the  shrinkage  of  the  cell,  and  from  the  quartan  by  its  dis- 
tinctly smaller  dimensions.  (Plate  XIII.,  Fig.  1.)  In  fresh  speci- 
mens the  young  ameboid  body  usually  shows  a  low  refractive  index  as 
compared  with  the  tertian  and  quartan  parasites.  It  is  never  pig- 
mented. Associated  with  the  inter-cellular  spores  there  are  frequently 
seen  in  the  plasma  small  spheroidal  bodies  exhibiting  an  active  roll- 
ing motion  and  occasional  blunt  projecting  points  (pseudopodia  ?),  and 
which  on  becoming  arrested  by  contact  with  the  red  cells  are  found  to 
be  indistinguishable  from  compact  intra-cellular  bodies.  The  positive 
identification  of  these  extra-cellular  bodies,  however,  appears  to  the 
writer  a  very  hazardous  undertaking.  (Cf.  Ziemann,  p.  49.)  In  dried 
specimens  stained  by  Nocht's  method,  however,  the  young  extra-cellu- 
lar parasite  may  be  positively  identified  from  the  presence  of  a  mass  of 
chromatin.  In  the  writer's  specimens  such  extra-cellular  bodies  were 
very  rarely  encountered. 

The  Estivo-autumnal  Signet-ring. — At  a  very  early  period  of  its  de- 
velopment the  estivo-autumnal  parasite  assumes  a  very  characteristic 
ring  shape.  Many  of  these  rings  early  develop  a  thickening  of  one 
segment,  and  to  these  bodies  of  various  sizes  the  term  "  signet-ring  " 
very  aptly  applies.     (Plate  XIII.,  Figs.  5—7.) 

It  is  to  be  noted  that  in  some  cases  the  rings  fail  to  exhibit  this 
thickening  but  remain  of  a  uniform  but  very  fine  caliber  throughout. 
(Plate  XIII.,  Fig.  4.)  The  period  during  which  the  rings  retain  this 
uniform  caliber  has  not  been  determined,  but  bodies  of  this  type  may 
be  seen  measuring  at  least  3  /i  in  diameter.  They  nearly  always  pre- 
sent two  nuclear  bodies,  lying  at  opposite  poles  or  close  together.  Oc- 
casionally such  rings  are  found  to  have  unfolded,  and  to  be  stretched 
like  a  thread  clear  across  the  cell,  the  nuclei  appearing  at  inconstant 
intervals. 

In  other  cases  no  rings  of  this  type  are  seen,  all  showing  the  thick- 
ening of  the  signet  and  a  single  nuclear  body.  In  the  majority  of 
cases  rings  of  both  types  are  associated  in  variable  numbers. 

Multiple  infection  with  the  young  rings  is  very  common  in  the 


390  3fALARIA. 

red  cells  of  most  cases  of  estivo-autumnal  malaria,  and,  as  a  rule,  its 
frequency  is  proportionate  to  the  severity  of  the  disease.  In  the  periph- 
eral blood  three  parasites  are  often  found  in  the  same  red  cell,  and  occa- 
sionally four,  while  in  smears  of  the  marrow  of  a  fatal  case,  seen  by 
the  writer,  infection  of  one  cell  with  four  rings  was  common,  five  par- 
asites were  occasionally  seen  in  the  same  cell,  and  one  slightly  swollen 
red  cell  was  encountered  containing  seven  well-formed  rings.  These 
observations  accord  with  the  reports  of  Ziemann  (p.  49),  who  found 
often  three  and  four  parasites,  and  once  as  many  as  five  in  one  cell. 

It  appears  in  the  description  of  the  hemameba  immaculata,  which  is  said 
to  sporulate  without  producing  pigment,  that  most  of  the  rosettes  contain 
comparatively  few  spores,  averaging  from  6  to  10.  (Marchiafava,  Bignami, 
Ziemann,  Marchoux,  Grassi  and  Feletti.)  The  close  resemblance  to  a  non- 
pigmented  rosette  presented  by  some  of  these  red  cells  harboring  5,  6,  or  7 
young  parasites  is  very  striking.  In  the  writer's  specimens  (see  Plate  XIII,, 
Fig.  2)  there  could  be  no  doubt  as  to  the  proper  interpretation  to  be  placed  on 
these  examples  of  multiple  infection. 

Multiple  infection  of  the  red  cell  appears  in  rather  rare  instances  to 
lead  to  the  development  of  a  peculiar  form  of  the  young  estivo-au- 
tumnal parasite  on  which  Mannaberg  bases  his  unique  theory  of  the 
development  of  crescents.  This  body  consists  in  the  apparent  union 
of  two  rings  by  a  fusion  of  their  nuclear  bodies.  (See  Plate  XIII.,  Fig. 
3.)  Mannaberg  depicts  all  transition  forms  between  these  bodies  and 
the  fully  developed  crescent. 

The  signet-ring  forms  frequently  reach  a  diameter  of  4  /^  while  still 
retaining  the  peculiar  thickening  of  one  segment,  the  thin  geometrical 
bow,  and  a  very  distinct  nuclear  body  staining  with  methylene-blue 
and  surrounded  by  a  narrow  achromatic  zone.    (Plate  XIII.,  Fig.  6.) 

The  distinguishing  features  between  the  estivo-autumnal  and  the 
tertian  rings  have  been  enumerated  under  the  description  of  the  latter 
parasite. 

Beyond  this  size,  when  persisting  in  the  finger  blood,  the  growth  of 
the  parasite  produces  an  irregular  body  in  which  the  outline  of  the 
ring  becomes  more  or  less  obscure.  The  full  development  of  the  large 
signet-rings  appears  to  require  about  24  hours. 

In  the  majority  of  ca.ses  the  ring  forms  seen  in  the  peripheral  blood 
fail  to  show  any  trace  of  pigment,  especially  in  the  patients  showing 
distinctly  intermittent  quotidian  or  tertian  paroxysms.  In  a  consider- 
able number  of  instances,  however,  especially  in  very  severe  and  fatal 
infections,  the  largest  rings  exhibit  a  very  few  minute  pigment  grains, 
usually  associated  with  older  pigmented  forms. 

Later  Stages  of  the  Estivo-autumnal  Parasite. — The  later  forms  of 
the  estivo-autumnal  parasite  are  rather  rarely  seen  in  the  peripheral 
circulation. 

Most  of  the  Italian  writers  speak  of  their  occurrence  in  the  finger  Mood 
as  being  very  unusual  but  not  unknown.  SaccharofF  in  two  cases  of  estivo- 
autumnal  infection  saw  many  rosettes  in  the  peripheral  blood.  Ziemann 
reports  that  in  malignant  tertian  cases  occurring  in  Italy  he  could  follow  in 


PLATE    Xiri. 


Cycles   of  Kstivo-autuiTinal    Parasite. 


Fig. 
Fig. 
Fig. 
Fig. 
Fig. 
Figs 
Figs 
Figs 

Figs 
Fig. 
Fig. 
Figs 
Fig. 
Figs 
Fig. 
Fig. 

Fig. 
Fig. 


1.  Very  j'oung  form. 

2.  Infection  of  one  cell  with  seven  young  parasites.     ( Drawn  from  a  marrow  smear.) 

3.  Triple  infection.     Two  parasites  joined  by  single  chromatin  mass. 
Double  infection.      Peculiar  rings  with  two  chromatin  grains  at  opposite  poles. 
Double  infection.     Small  ring  adherent  to  cell. 

7.     Signet-ring  forms.     Sub-division  of  chromatin. 

9.     Later  ring  forms,  with  sub-divided  chromatin  and  few  pigment  grains. 


4- 
5- 
6, 
.  8, 
.  10-12. 


Full-grown  forms  with  finely  sub-divided  chromatin  and  gradual  concentration  of 
pigment. 
13,  14.      Stages  of  presegmenting  forms,  with  concentrated  eccentric  pigment. 

15.  Double  infection  with  separate  presegmenting  bodies. 

16.  Estivo-autumnal  rosette. 

.17,  18.     Young  crescent  and  ovoid. 
19.     "  Pulsating  "  crescent. 
.  20-22.     Various  forms  of  crescents. 
23.     Two  bows  about  single  crescent. 

Fully  developed   crescent  ;  two   masses  of  chromatin  ;    achromatic   substance  ;    double 
wreaths  of  pigment. 

Diagrammatic  flagellating  body. 

Extra-cellular  sterile  body.  ' 


24. 

25- 
26. 


THE  ESTIVO-AUTUMNAL  PARASITE.  391 

the  blood  the  complete  cycle,  but  that  in  cases  occurring  in  Kamerun  the 
later  forms  were  not  found  in  the  finger  blood.  Plehn  describes  a  variety 
of  parasite  which  he  believes  is  peculiar  to  hemoglobinuric  fever,  and  of 
which  the  later  forms  are  of  very  small  size  but  abundantly  represented  in 
the  peripheral  blood.  In  five  cases  examined  by  the  writer  the  entire  de- 
velopmental cycle  of  the  estivo-autumnal  parasite  could  be  followed  in  the 
peripheral  blood,  and  on  the  forms  observed  in  these  cases  is  based  the 
present  description  of  the  later  phases  of  this  parasite. 

After  the  ring  has  reached  its  full  size  (4  //,  24  hours  +)  the  swollen 
segment  begins  to  increase  in  bulk  and  to  involve  a  larger  portion  of 
the  circumference,  yielding  forms  seen  in  Plate  XIII.,  Figs.  8  and  9. 
Some  of  these  forms  closely  resemble  the  turban-shaped  rings  of  the 
tertain  parasite  (Plate  XIII.,  Fig.  8),  but  are  much  smaller.  A  few 
fine  pigment  grains  were  usually  found  scattered  along  the  periphery 
of  the  growing  segment.  Forms  corresponding  to  the  full-grown  ter- 
tain parasite  with  homogeneous  body  are  rarely  seen  in  the  peripheral 
blood.  When  encountered  they  are  found  to  occupy  three-fourths  of 
the  shrunken  cell,  stain  homogeneously  with  methylene-blue,  and  fail 
to  exhibit  a  distinct  nuclear  body  after  methylene-blue  or  hema- 
toxylon. 

Most  of  the  larger  forms  of  the  parasite  seen  in  the  peripheral 
blood  give  evidence  of  approaching  segmentation,  exhibiting  a  distinctly 
reticular  structure  and  a  condensation  of  pigment  into  one  or  two 
clumps.  (Plate  XIII.,  Fig.  10.)  In  many  of  these  bodies  the  original 
ring  persists  at  one  segment  of  the  parasite,  but  appears  to  be  of  re- 
duced size,  and  is  sometimes  subdivided  by  strands  of  protoplasm. 
The  nuclear  body  at  this  period  fails  entirely  to  stain  with  methylene- 
blue  and  is  indistinct  after  hematoxylon,  resembling  in  this  respect  the 
full  grown  homogeneous  tertain  organism.  The  presence  of  a  distinct 
achromatic  spot  adjoining  the  clump  of  pigment  is  very  frequent  in 
these  forms,  and  this  spot  is  found  by  Nocht's  stain  to  be  composed  of 
chromatin  granules. 

The  further  development  of  the  pre-segmenting  forms  is  represented 
in  Plate  XIII.,  Figs.  11-15,  two  separate  parasites  in  the  same  red  cell 
being  occasionally  seen.  In  them  the  reticular  structure  becomes  more 
distinct,  the  pigment  is  still  further  concentrated,  and  the  subdivided 
nuclear  bodies  appear  as  small  achromatic  spots  in  the  meshes  of  the 
reticulum  and  again  stain  distinctly  with  hematoxylon. 

Estivo-autumnal  rosettes  appear  in  the  peripheral  blood  of  rare 
cases  only  and  in  moderate  numbers,  and  exhibit  a  very  uniform  struc- 
ture. 

The  pigment  is  grouped  in  a  central  granular  clump,  or,  rarely, 
somewhat  scattered.  The  spores  seem  to  be  arranged  in  two  rows,  but 
this  appearance  is  probably  an  optical  effect  produced  by  the  flattening 
of  the  more  or  less  spheroidal  body  of  the  rosette,  the  spores  origi- 
nally lying  in  the  central  axis  of  the  rosette,  falling  in  the  hardening 
process,  within  those  lying  on  the  periphery. 

When  admitting  of  accurate  enumeration  their  numbers  are  found 
to  vary  between  18  and  21.     The  same  number  of  spores  was  repeat- 


392  MALARIA. 

edly  counted  in  favorable  specimens,  made  by  the  writer  from  the 
marrow  of  a  fatal  case.  In  sections  of  the  tissues  of  fatal  cases,  how- 
ever, the  number  of  spores  appears  to  vary  between  wider  limits,  i.  e., 
8  to  20,  but  as  the  entire  rosette  need  not  always  be  included  in  the 
section  the  observations  made  in  smears  are  the  more  reliable.  A  rim 
of  hemoglobin  invariably  surrounds  the  rosette  and  strands  of  hemo- 
globin are  frequently  fouifd  running  between  the  spores  for  a  variable 
distance,  sometimes  within  the  outer  row. 

These  rosettes  differ  from  the  tertian  segmenting  forms  in  the  smaller 
size  of  the  body  and  shrunken  appearance  of  the  cell,  and  in  the  small  size, 
but  not  in  the  number,  of  the  spores. 

The  Changes  in  the  Chromatin  of  the  Estivo-autumnal  Parasite. — 
In  the  young  ring  forms  the  early  subdivision  of  the  chromatin  has  been 
noted  by  Gautier,  and  in  the  writer's  specimens  was  a  prominent  differential 
character  from  the  tertian  rings.  A  great  variety  of  appearances  is  pro- 
duced by  the  irregular  subdivision  and  distribution  of  the  chromatin  in  the 
young  estivo-autumnal  parasite,  many  of  which  have  been  sketched  or  de- 
scribed for  the  tertian  rings.  The  grains  are  usually  quite  small  and  are 
sometimes  apparently  fused  into  a  spindle-shaped  mass,  lying  within  the 
ring.  Other  peculiarities  which  may  be  noted  are  :  a  markedly  unequal  size 
of  the  grains,  a  widely  separate  position,  a  frequent  concentration  in  the 
center  of  the  ring,  and  very  rarely,  a  complete  absence  of  chromatin. 

After  24  hours'  growth,  the  chromatin  granules  become  more  numerous 
and  extremely  minute,  and  are  inclosed  in  a  trace  of  the  milky  substance,  as 
in  the  tertian  parasite. 

The  changes  in  the  chromatin  in  the  pre-segmenting  estivo-autumnal 
body  are  similar  to  those  of  the  tertian  parasite.  In  some  of  the  writer's 
specimens  the  chromatin  granules  were  found  in  radiating  lines  stretching 
from  the  parent  mass  to  the  new  peripheral  groups.  In  many  specimens  the 
peripheral  groups  of  granules  were  well  formed  while  the  central  portions 
of  the  body  contained  many  diffuse  granules.  The  relative  quantity  of 
chromatin  in  some  of  these  bodies  appears  surprisingly  large.  The  spores 
in  the  mature  rosette  usually  contain  single  compact  grains  of  chromatin 
which  stain  readily  by  methylene-blue,  but  in  some  rosettes  two  large  gran- 
ules of  chromatin  are  seen  in  a  few  spores  although  the  rosette  seems  ready 
to  burst. 

The  double  nuclei  seen  in  many  young  estivo-autumnal  rings  may  per- 
haps be  referred  to  the  incomplete  fusion  of  the  chromatin  in  the  rosette. 

Characters  of  the  Pigment  of  Estivo-autumnal  Parasites. — When  any 
considerable  quantity  of  pigment  gathers  in  the  estivo-autumnal  para- 
site it  is  usually  found  in  one  or  two  groups,  but  rarely  is  diffuse. 

When  the  parasite  has  reached  the  full-grown  homogeneous  stage 
the  pigment  is  commonly  found  concentrated  in  a  single  compact  mass. 
This  early  concentration  of  pigment  is  one  of  the  chief  features  which 
distinguish  the  estivo-autumnal  from  the  tertian  parasite,  in  the  pre- 
segmenting  stage.  This  fact  has  been  fully  emphasized  by  Gautier, 
and  was  very  uniformly  illustrated  in  the  writer's  cases. 

The  Plurality  of  Species  in  the  Estivo-autumnal  Group  of  Para- 
sites.— The  probability  that  several  species  of  parasites  are  concerned 
in  the  severe  types  of  malarial  fever  prevailing  in  tropical  countries, 
especially  in  the  summer  and  autumn,  has  been  chiefly  maintained  by 


THE  ESTIVO-AVTUMNAL  PARASITE.  393 

the  Italian  school,  who  divide  this  group  of  parasites  into  two  species  : 
(1)  the  quotidian  and  (2)  the  malignant  tertian. 

1 .  The  Quotidian  Parasite. — The  typical  fever  curve  of  this  variety 
is  rather  rarely  seen,  more  frequently  in  relapses  than  in  initial  seiz- 
ures, while  a  postponement  of  paroxysms  is  usually  observed,  and  a 
continuous  fever  is  very  common.  The  typical  attack  is  short,  the 
fever  lasting  6-8,  rarely  12  hours,  the  temperature  then  falling  to 
37°  C. 

The  descriptions  of  the  morphology  of  this  parasite  unfortunately 
refer  only  to  its  appearance  in  fresh  blood.  During  the  rise  of  the  tem- 
perature, the  sweating  stage,  and  the  first  hours  of  apyrexia,  the  blood 
is  found  to  contain  a  variable  number  of  red  cells  infected  with  one  or 
more  very  actively  motile,  or  non-motile,  parasites  of  discoidal  or  ring 
shape.  During  the  afebrile  period  the  parasites  increase  in  size,  the 
ameboid  motion  diminishes  or  ceases,  and  fine  pigment  grains  are  de- 
posited along  the  periphery  of  the  organism.  Later,  in  the  larger 
forms,  the  pigment  gathers  in  a  single  clump  or  heap  of  grains.  Dur- 
ing the  entire  development,  the  infected  red  cell  diminishes  in  size  and 
presents  a  "  brassy  "  color  as  a  result  of  "  acute  necrosis  "  induced  by 
the  parasite.  Rosettes  are  seldom  encountered  in  the  finger-blood, 
segmentation  occurring  principally  in  the  internal  organs,  as  seen  in 
the  aspirated  splenic  blood.  Rarely,  segmentation  occurs  before  pig- 
mentation, but  usually  the  numerous  round  or  oval  spores  are  found 
grouped  about  a  central  pigment  mass,  the  rosettes  being  much  smaller 
than  those  of  the  quartan  or  mild  tertian  parasites. 

Contrary  to  the  rule  in  malignant  tertian  infections,  the  young  para- 
sites are  found  in  the  blood  from  the  beginning  of  the  paroxysm,  and, 
except  in  very  mild  cases,  there  is  no  period  in  the  cycle  when  the 
parasites  are  absent  from  the  finger  blood. 

2.  The  malignant  tertian  parasite  is  distinguished  on  both  clinical 
and  morphological  grounds.  Clinically  the  typical  paroxysm  begins 
with  a  sharp  elevation  to  about  40°  C,  the  febrile  period  lasts  24  or 
36—40  hours,  is  marked  by  a  pseudocrisis  and  preoritical  elevation,  the 
fever  describing  in  the  three  hourly  chart  a  very  characteristic  course 
which  differs  from  that  of  the  mild  tertian  paroxysms.  A  tendency 
toward  various  irregularities  is  common. 

In  the  blood  the  parasites  may  be  scarce  or  even  entirely  absent  at 
the  beginning  of  the  paroxysm.  At  the  height  of  the  fever  the  red 
cells  contain  small  non-motile  ring  or  disc-shaped  bodies,  or  irregular 
ameboid  bodies,  which  begin  to  show  pigmentation  toward  the  ap- 
proach of  the  afebrile  period.  Most  of  the  parasites  then  disappear 
from  the  finger  blood,  and  rosettes  are  rarely  seen  except  in  some  very 
rich  infections.  The  pre-segmenting  forms  are  round  or  ovoid,  one- 
fourth  to  one-half  the  size  of  the  red  cell,  and  the  pigment  is  gathered 
in  a  single  clump  or  in  a  mass  of  vibrating  granules.  The  rosettes 
occupy  about  two-thirds  of  the  red  cell,  and  exhibit  two  rows  of  spores 
which  usually  number  10-12,  rarely  15-16.  The  infected  cells  are 
markedly  shrunken  and  present  a  "  brassy  or  golden  "  appearance. 


394  MALARIA. 

The  authors  distinguish  the  malignant  tertian  parasite  from  the  com- 
moner or  mild  variety  on  the  following  features. 

1.  The  malignant  tertian  parasite  is  smaller  in  all  stages.  2.  Its 
pigment  is  less  abundant  and  often  non-motile,  while  in  the  other  the 
pigment  is  very  abundant  and  always  in  vibratory  motion.  3.  The 
rosettes  are  smaller,  contain  only  10-12  (rarely  16)  spores,  and  are 
rarely  seen  in  the  finger  blood.  4.  The  infected  cell  is  shrunken  in- 
stead of  being  swollen,  as  with  the  mild  tertian  infection. 

From  the  quotidian  parasite  the  malignant  tertian  is  distinguished 
on  the  following  grounds. 

1.  The  tertian  ameba  is,  in  corresponding  stages,  larger  and  less 
transparent  than  the  quotidian. 

2.  In  the  malignant  tertian  parasite  the  ameboid  movement  is  lire- 
lier,  so  that  the  resting  discoidal  forms  are  less  frequent  than  with  the 
quotidian  parasite.  The  larger  pigmented  tertian  forms,  also,  are  often 
ameboid,  this  property  persisting  for  24  hours  or  longer. 

3.  The  pigment  in  the  tertian  parasite  is  often  vibratory,  but  never 
in  the  quotidian. 

4.  In  the  quotidian  rosettes  pigment  is  sometimes  wanting. 

5.  The  appearance  in  the  finger  blood  of  a  new  generation  of  ter- 
tian parasites  is  seen  some  hours  after  the  beginning  of  the  paroxysm, 
therefore  much  later  than  with  the  quotidian  infection. 

Marchiafava  and  Bignami  admit  that  the  similarity  between  the  malignant 
tertian  and  the  quotidian  parasites  is  very  great  and  that  the  differential 
diagnosis  is  difficult  and  possible  only  from  the  full-grown  forms  seen  just 
before  the  paroxysm.  They  apparently  do  not  feel  quite  certain  that  the 
quotidian  and  malignant  tertian  parasites  are  separate  species,  as  is  indi- 
cated by  the  following  extract  from  their  discussion  on  this  point.  (Syd. 
Soc.  Transl.,  p.  88.) 

"The  remarkable  points  of  resemblance  between  the  quotidian  and  ma- 
lignant tertian  parasites  make  it  very  difficult  to  solve  the  question  whether 
we  have  to  do  with  different  sorts  of  parasites  in  the  strict  sense,  or  with 
one  and  the  same  parasite  which  varies  greatly  in  the  time  of  its  develop- 
ment, 24-48  hours — and  there  are  all  intermediate  degrees.  On  this  latter 
theory  it  becomes  easy  to  ascribe  the  morphological  differences  to  the  vary- 
ing length  of  the  cycle.  But  various  facts  oppose  this  hypothesis.  First, 
the  clinical  types  of  the  quotidian  and  tertian  are  clearly  distinct  from  each 
other,  and  have  a  certain  stability  which  is  maintained  in  relapses  and  re- 
currences. Second,  we  have  never  met  with  intermediate  forms  or  transi- 
tional cases,  although  it  is  very  difficult  to  interpret  the  irregular  fevers. 
Granting  that  the  question  cannot  at  present  be  solved  definitely  *  *  *  we 
are  inclined  to  adopt  the  view  that  the  ameba  of  the  quotidian  and  the 
ameba  of  the  summer  tertian  are  closely  related  varieties  of  one  and  the 
same  parasite. ' ' 

This  view  is  not  materially  altered  in  the  authors'  last  treatise  (1900). 

Mannaberg,  and  Grassi  and  Feletti  accept  the  views  of  Marchiafava 
and  Bignami  and  describe  a  quotidian  parasite,  but  do  not  furnish 
original  observations  tending  to  confirm  their  opinions.  Thayer  and 
Hewetson,  Ziemann,  and  Gautier,  all  of  whom  have  studied  very  mi- 
nutely the  estivo-autumnal  parasites,  the  latter  authors  from  extremely 


THE  ESTIVO-AUTUMNAL  PARASITE.  395 

rich  material  in  tropical  regions,  fail  to  find  sufficient  grounds  for  the 
subdivision  of  the  group. 

From  the  writer's  study  of  cases  at  Montauk  among  soldiers  re- 
cently arrived  from  Cuba  in  1898,  it  was  concluded  that  it  is  impos- 
sible from  the  observation  of  parasites  in  the  peripheral  blood  to  dem- 
onstrate the  existence  of  a  24-hour  cycle,  since  the  infecting  broods 
are  seldom  compact.  Quotidian  paroxysms  always  seemed  to  be  refer- 
able to  infection  with  two  broods  of  malignant  tertian  amebse. 

Two  features  were  noted,  however,  which  offered  some  hope  of  dis- 
tinguishing a  quotidian  from  the  tertian  parasite. 

1.  The  exclusive  presence  in  a  few  instances  of  rings  with  double 
nuclei  and  without  the  signet. 

2.  The  appearance  of  large  numbers  of  very  small  adult  parasites 
in  the  peripheral  blood. 

Neither  of  these  features  proved  sufficient  for  the  positive  identifi- 
cation of  a  quotidian  parasite.  The  peculiar  rings  were  usually  asso- 
ciated with  the  ordinary  signet-ring  forms,  and  the  rosettes  seen  in 
peripheral  blood  were  identical  in  appearance  with  those  found  in 
marrow-smears  from  fatal  cases  of  malignant  tertian  infectio  n. 

It  therefore  seems  necessary  to  conclude  for  the  present  that  a  spe- 
cial quotidian  parasite  has  not  yet  been  demonstrated  and  probably  does 
not  exist.  As  stated  by  Ziemann,  it  seems  likely  that  estivo-autumnal 
fever  is  caused  by  a  single  species  of  parasite  whose  developmental 
cycle  usually  requires  48  hours,  but  may  possibly  be  completed  in  24, 
or,  as  in  one  of  his  cases,  may  be  prolonged  to  72  hours. 

The  Hemameba  Immaculata. — Grassi  and  Feletti,  Marchiafava, 
Celli  and  Bignami,  Guarnieri,  Sacharoff,  Marchoux,  and  Ziemann  re- 
port cases  in  which  rosettes  were  found  in  the  blood  or  viscera  which 
were  free  from  pigment.  Most  of  these  authors,  while  admitting  that 
the  parasites  may  occasionally  sporulate  without  producing  pigment, 
are  not  inclined  to  regard  the  hemameba  immaGulata  as  a  separate 
species.  Grassi  and  Feletti  claim  to  have  observed  in  a  bird  exclusive 
infection  with  a  variety  of  parasite  which  fails  to  produce  pigment, 
and  regard  the  appearance  in  the  human  subject  of  rosettes  without 
pigment  as  evidence  of  infection  by  a  distinct  variety  of  parasite. 
Mannaberg  also  accepts  this  classification. 

In  the  report  of  the  examination  of  the  viscera  of  this  bird  no  mentiou 
is  made  of  the  presence  or  absence  of  pigment,  and  it  is  impossible  to  deter- 
mine whether  or  not  the  infection  had  failed  to  produce  pigment  in  the  vis- 
cera as  well  as  in  the  peripheral  blood. 

In  all  cases  in  which  pigment-free  rosettes  have  been  found  in  the 
blood  of  human  subjects  there  have  been  found  the  usual  pigment  de- 
posits, and  pigmented  rosettes,  in  the  viscera.  That  there  is  consider- 
able variation  in  the  quantity  of  pigment  produced  by  the  parasite  in 
fatal  cases  is  shown  by  the  reports  by  Marchiafava  and  Bignami  of 
fatal  cases  in  which  a  microscopical  examination  was  required  to  show 
the  presence  of  very  scanty  deposits  in  the  viscera. 


396  MALABIA. 

Ziemann  mentions  that  he  has  seen  a  pre-segmenting  body  of  the 
benign  tertian  type  which  was  entirely  free  from  pigment. 

The  writer  believes  that  some  examples  of  multiple  infection  of  red 
cells  have  been  mistaken  for  pigment-free  rosettes,  but  this  explana- 
tion can  hardly  apply  to  the  reports  of  many  such  rosettes  in  the  cere- 
bral capillaries.  The  majority  of  observers,  including  Marchiafava 
and  Bignami  believe  that  there  is  no  pigment-free  variety  of  human 
malarial  organism  but  that  the  estivo-autumnal  parasites  may  occa- 
sionally fail  to  elaborate  pigment. 

The  Crescentic  Bodies. 

On  the  4th-6th  days  of  any  but  initial  paroxysms  of  estivo-autum- 
nal infection  the  peripheral  blood  may  contain  red  cells  infected  by 
spheroidal,  oval,  elliptical,  or  small  crescentic  bodies  which  represent 
the  early  forms  of  the  sexual  cycle  of  the  parasite.  The  relation  of 
these  forms  to  the  young  ameba  is  not  clear  and  it  is  not  known 
whether  the  crescents  develop  directly  from  the  spores  or  from  some 
parent  body,  such  as  is  seen  with  various  coccidia,  and  in  which  the 
young  'parasites  are  of  crescentic  form  before  their  discharge  from  the 
mother  cell.  The  latter  view  is  the  more  probably  correct,  being 
favored  by  analogy,  but  the  earliest  forms  of  crescents  are  very  fre- 
quently spheroidal  or  elliptical.  On  the  other  hand,  neither  direct 
observation  nor  analogy  favor  the  view  that  they  spring  directly  from 
the  ordinary  ameboid  parasites  of  the  pyrogenous  cycle,  as  claimed  by 
Marchiafava,  Celli,  and  Bignami. 

Mannaberg  regards  the  crescents  as  the  syzygia  developing  from  the 
union  of  two  young  parasites,  and  while  this  view  is  lacking  in  sup- 
port from  the  actual  demonstration  of  two  parasites  uniting  to  form 
the  crescent,  and  is  entirely  contrary  to  the  recognized  mode  of  origin 
of  homologous  forms  in  other  protozoa,  there  are  some  morphological 
features  which  are  somewhat  in  its  favor.  These  are  the  appearance, 
frequently,  of  two  groups  of  pigment,  occasionally  of  two  masses  of 
chromatin,  and  the  isolated  observation  of  two  halters  with  one 
crescent. 

Appearing  first  as  bodies  somewhat  shorter  than  the  diameter  of  the 
red  cell,  through  various  changes  in  length,  breadth,  and  shape  (see 
Plate  XIII. ),  the  adult  crescent  is  developed,  appearing  in  the  blood 
usually  after  the  fifth  to  the  seventh  days  of  the  paroxysm.  The 
average  adult  crescent  measures  about  9-12  /i  in  length,  by  2-3//  in 
breadth,  but  in  some  cases  very  large  or  giant  crescents  have  been 
observed,  the  writer  having  seen  specimens  measuring  20 /i  x  5//. 
While  the  young  crescent  contracts  and  swells,  altering  its  shape,  the 
older  forms  are  quiescent,  and  neither  show  true  ameboid  properties. 
The  ends  are  either  pointed  or  blunt,  many  old  specimens  appearing  with 
swollen  ends. 

The  pigment  is  in  the  form  of  coarse  golden  yellowish  grains,  rods, 
or  possibly  at  times  in  rod-shaped  crystals.     It  is  the  coarsest  pigment 


FLAGELLATE  BODIES.  397 

elaborated  by  the  parasite  and  is  always  more  abundant  than  in  the 
ameboid  bodies  of  equal  size.  It  is  arranged  in  a  single  central  mass 
or  circle,  or  as  a  double  circle  resembling  a  figure  8.  Occasionally  it 
is  found  in  scattered  groups,  especially  in  very  large  crescents. 

Although  a  membrane  cannot  be  said  to  exist  about  the  crescent,  yet 
its  outer  border  may  be  stained  reddish  by  eosin,  and  it  has  therefore 
been  supposed  that  a  remnant  of  Hb  surrounds  the  crescent  on  all 
sides.  The  membrane  or  thickened  outer  border  of  the  red  cell  is 
closely  applied  about  the  convex  side  of  the  crescent,  while  across  the 
concavity  it  stretches  loosely  like  a  halter.  The  writer  has  seen  two 
of  these  halters  spanning  equal  segments  of  the  concavity  of  a  single 
large  crescent  (Plate  XIII.,  Fig.  23),  while  Marchiafava  and  Bignami 
have  seen  two  adult  crescents  within  a  single  cell. 

In  the  center  of  the  crescent  is  a  sharply  marked,  light  blue  staining, 
or  achromatic  area  of  variable  size,  containing  the  chromatin  and 
usually  also  the  pigment.  Marchiafava  and  Bignami  describe  the 
nucleus  of  the  crescent  as  vesicular,  but  for  reasons  already  stated  the 
writer  is  unable  to  regard  the  nucleus  as  consisting  of  any  other  struc- 
ture than  the  mass  of  chromatin  granules,  which  can  always  be  found 
in  living  crescents.  In  the  young  crescent  tliese  chromatin  granules 
are  of  larger  size  than  in  the  adult  body,  in  which  they  become  sub- 
divided, and,  when  obscured  by  pigment,  extremely  difficult  to  detect. 
Sometimes  there  are  two  separate  groups  of  chromatin  granules. 
Marchiafava  and  Bignami  expose  most  specimens  containing  cres- 
cents in  a  moist  chamber  for  a  few  minutes,  thereby  causing  the  pig- 
ment to  separate,  the  nucleus  to  swell,  and  the  chromatin  granules 
to  be  more  apparent.  With  Nocht's  method  this  expedient  is  seldom 
necessary. 

Although  crescents  may  show  transverse  segmentation  and  occasion- 
ally lateral  budding,  these  changes  are  probably  degenerative,  as  is 
also  their  vacuolation.  Former  views  regarding  their  multiplication 
by  various  methods  are  uoav  known  to  be  erroneous. 

That  the  marrow  is  a  special  seat  of  the  development  of  crescentic 
bodies  is  believed  by  Councilman,  Bignami,  and  Bastianelli,  who  have 
found  an  excessive  number  of  young  forms  in  this  tissue  when  they 
were  scarce  elsewhere. 

The  long  persistence  of  crescents  in  the  blood  and  their  resistance  to 
quinine  are  matters  of  common  clinical  observation.  Yet  Leukowicz, 
who  describes  several  varieties  of  crescents,  denies  that  they  are  any 
more  refractory  to  quinine  than  are  the  ameboid  forms. 

Flagellate  Bodies. 

When  blood  containing  crescents  is  allowed  to  stand  in  the  air  or 
under  a  cover-glass  for  a  few  moments  some  of  the  crescents  slowly 
assume  the  spheroidal  form,  active  vibratory  oscillations  of  the  pig- 
ment granules  begin,  and  soon,  from  one  or  more  points,  pscudopodia 
shoot  out  with  active  lashing  movements.     These  flagella  continue  their 


398  MALAEIA. 

movements  for  some  time,  changing  their  position  actively,  their  shape 
slowly,  while  some  may  be  seen  to  break  off  from  the  body  and  swim 
off  through  the  plasma.  The  formation  of  flagellate  bodies  represents 
the  second  stage  in  the  sexual  cycle,  probably  never  occurring  in  the 
human  body. 

These  flagellate  bodies  are  found,  on  staining,  to  be  composed  of  a 
spheroidal  pigmented  mass,  usually  surrounded  by  a  remnant  of  the 
red  cell,  of  2  to  4  flagella  of  variable  type,  of  one  or  more  lateral  buds, 
and  of  chromatin,  which  has  now  undergone  a  remarkable  transforma- 
tion. The  bulk  of  chromatin  is  apparently  much  increased,  and  most 
of  it  is  usually  found  in  the  form  of  long  slender  threads  within  the 
flagella.  Occasionally  short  threads  of  chromatin  may  be  found  within 
the  sphere.  The  flagella  are  composed  of  an  outer  protoplasmic  cover- 
ing, their  ends  are  blunt  or  pointed,  their  borders  even  or  bulbous,  and 
while  most  of  them  contain  chromatin  threads,  some  are  entirely  lack- 
ing in  this  constituent. 

Not  all  crescents  develop  flagella,  some  remain  in  the  semilunar 
form,  exhibit  slow  undulatory  movements,  and  tend  to  stain  more 
deeply  with  methylene-blue.  It  is  believed  that  these  crescents  are 
penetrated  by  a  motile  flagellum,  after  which  they  become  actively 
locomobile,  and  it  is  further  supposed  that  these  motile  fertilized 
crescents  or  "  vermiculi "  are  capable  of  penetrating  the  wall  of  the  mos- 
quito's stomach,  and  there  developing  the  encysted  bodies,  which  are 
the  next  stage  of  the  bi-sexual  growth  of  the  parasite. 

The  evidence  on  which  this  relation  of  two  varieties  of  crescents  is  indi- 
cated is  largely  derived  from  analogous  phenomena,  known  to  occur  among 
various  coccidia.  Simond  and  Siedlecki,  in  the  coccidia,  have  seen  the  fer- 
tilization of  one  crescentic  body  by  the  motile  flagellum  of  another,  and 
MacCallum,  examining  the  parasites  of  crows,  has  seen  the  entrance  of  a 
flagellum  into  a  crescent  with  the  development  of  a  motile  vermiculus.  (Cf. 
Solley  and  Carter.)  The  same  evidence  indicates  that  the  flagella  are  mo- 
tile chromosomes  of  a  karyokinetic  nucleus,  and  that  their  function  is  that 
of  a  male  fertilizing  element.  It  thus  appears  that  the  crescents  and  their 
flagellated  derivatives  constitute  a  divergent  developmental  series  destined 
to  perpetuate  the  species  in  the  body  of  the  mosquito. 

Tertian  flagellate  bodies  develop  from  the  full-grown  tertian  parasites 
in  mucii  the  same  way  as  from  crescents.  Of  full-grown  tertian  para- 
sites three  varieties  must  be  separated  :  (1)  Bodies  which  are  destined 
to  segment,  and  which  the  writer  believes  are  often  produced  by  con- 
jugation. (2)  Large  hyaline  forms  which  develop  flagella.  (3)  Large 
hyaline  forms  with  little  chromatin  which  probably  become  fertilized 
by  detached  flagella.  This  last  form  has  apparently  been  observed  in 
shed  blood  as  a  large  vacuolated,  apparently  sterile,  body,  but  its 
fertilization  has  never  been  observed. 

In  the  tertian  parasite  which  is  developing  flagella,  the  chromatin 
increases  in  quantity,  becomes  arranged  in  a  basket  network,  breaks 
up  into  several  coarse  filaments  which  may  be  found  protruding  from 
the  edge  of  the  sphere,  and  finally  these  filaments  are  discharged  in  the 
form  of  flagella,  of  which  there  are  usually  six  to  each  parasite. 


THE  MALARIAL  PARASITE  IN  THE  MOSQUITO.  399 

Quartan  parasites  develop  flagellate  bodies  very  similar  in  appear- 
ance to  those  of  the  estivo-autumnal  type. 

III.  The  Development  of  the  Malarial  Parasite  in  the  Mosquito. 

It  is  principally  owing  to  tlie  labors  of  Eoss,  at  Hanson's  suggestion, 
that  the  life  cycle  of  the  parasite  in  the  mosquito  has  been  elucidated.  Eoss 
followed  the  development  of  the  proteosoma  of  Labbe  in  the  tissues  of  mos- 
quitoes which  had  fed  upon  the  blood  of  birds  containing  this  malarial  para- 
site. He  traced  the  development  of  an  encysted  body  in  the  wall  of  the 
intestine,  and  the  formation  therein  of  large  numbers  of  so-called  germinal 
rods.  Finally,  when  the  germinal  rods  were  found  abundantly  in  the  sali- 
vary glands,  the  complete  cycle  of  the  parasite  in  the  mosquito,  and  its 
natural  mode  of  access  to  the  human  body  were  made  clear.  The  demon- 
stration was  rendered  doubly  positive  when  Bignami  succeeded  in  transfer- 
ring the  estivo-autumnal  infection  from  one  human  being  to  another  by  pass- 
ing it  through  Anopheles  claviger,  a  species  of  mosquito  found  in  the  Eoman 
Campagna.     Later,  tertian  infection  was  transferred  in  the  same  manner. 

The  details  of  development  in  the  mosquito  have  been  worked  out 
principally  by  Grassi,  Bignami,  and  Bastianelli,  while  much  valuable 
information  regarding  the  few  dangerous  varieties  of  mosquitoes,  their 
habits,  and  the  means  of  identifying  and  destroying  them,  have  been 
contributed  by  Ross,  Nuttall,  the  Italian  writers,  and  by  the  Jenner 
School  of  Tropical  Medicine. 

Developmental  Forms. — Two  days  after  the  mosquito  has  fed  upon 
blood  containing  crescents,  there  are  to  be  found  in  the  intestinal  sub- 
mucosa  spindle-shaped,  oval,  or  spheroidal  bodies,  resembling  the 
spindle-shaped  bodies  of  the  blood.  They  contain  a  single  nucleus, 
scattered  pigment,  and  their  protoplasm  appears  vacuolated.  The 
actual  development  of  these  bodies  from  the  crescents  and  the  pene- 
tration of  fertilized  crescents  into  the  intestinal  wall  has  not  been 
demonstrated. 

By  the  third  to  fourth  days  the  bodies  are  much  enlarged,  distinctly 
encapsulated,  their  protoplasm  is  reticulated  and  their  pigment  has 
largely  disappeared. 

By  the  fifth  to  the  sixth  days,  the  encysted  bodies  have  greatly  in- 
creased in  size,  measuring  up  to  70  ju  in  diameter,  and  project  into  the 
celomic  cavity.  They  are  now  found  to  contain  numerous  nuclei  and 
globules  resembling  fat. 

By  the  seventh  day  fully  formed  germinal  rods  are  found  in  the 
cyst  in  enormous  numbers.  These  rods  average  about  14  /i.  in  length, 
their  ends  are  pointed,  and  at  the  center  of  each  is  a  granule  of  chro- 
matin. They  are  arranged  in  radiating  or  undulating  masses  about 
numerous  centers. 

After  the  seventh  day  broken  capsules  are  found  which  have  dis- 
charged their  rods  into  the  celom,  from  which  region  they  make  their 
way  into  the  salivary  glands. 

In  addition  to  encysted  bodies  which  develop  rods,  some  contain 
"  brownish  bodies  "  of  various  sizes,  the  nature  of  which  is  not  known. 


400  MALARIA. 

Very  similar  phases  have  been  described  for  the  development  of  the 
tertian  parasite,  while  Bignami  and  Bastianelli  have  recently  succeeded 
in  tracing  the  similar  phases  of  the  quartan  parasite. 

IV.    Conjugation  of  Malarial  Parasites. 

In  1897  the  writer's  attention  was  attracted  by  a  specimen  of  blood 
from  a  rich  tertian  infection  in  which  there  were  very  numerous  twin 
parasites  of  a  younger  brood  while  all  the  older  parasites  were  single. 
A  remarkable  specimen  of  this  type  was  secured  at  Montauk,  in  which 
both  broods  were  very  compact  and  very  numerous,  and  nearly  all  the 
younger  parasites  were  twinned,  while  all  the  older  forms  were  single. 
Extreme  length  and  variety  of  ameboid  processes  also  characterized 
the  younger  parasites  in  both  specimens.  Later  the  writer  was  able 
to  follow  such  a  case  through  one  complete  cycle  and  found  that  the 
young  twins  were  succeeded  by  full-grown  single  parasites  of  larger 
size.  Finally,  the  application  of  Nocht's  stain  furnished  convincing 
pictures  of  all  stages  of  union,  first  of  the  bodies,  later  of  the  nuclei 
of  the  twin  parasites,  and  left  no  room  for  doubt  that  under  some  con- 
ditions malarial  parasites  undergo  a  form  of  conjugation. 

The  phases  of  this  process  are  sketched  in  Plate  XIV. 

Usually  the  members  of  the  conjugating  pair  presented  distinct 
diiferences  in  appearance.  One  was  a  thick  compact  parasite  with 
abundant  cytoplasm,  one  large  and  sometimes  one  smaller  granule  of 
chromatin,  and  was  seldom  seen  in  the  ring  form.  The  other  was  a 
ring-shaped  parasite  of  delicate  contour,  of  larger  diameter  and  with 
rather  less  chromatin. 

The  separate  development  of  each  of  these  parasites  was  followed  in 
these  cases  up  to  the  large  spheroidal  bodies.  The  compact  parasite 
usually  retained  its  compact  form  throughout,  producing  a  parasite  re- 
sembling in  size  the  quartan  forms,  and  staining  very  densely  with 
methylene-blue.  In  some  instances  it  developed  6  or  8  separate 
masses  of  chromatin  granules,  but  the  writer  could  not  be  certain  that 
it  sporulated.  The  delicate  rings,  developing  singly,  produced  medium- 
sized,  pale-staining  parasites  of  full-grown  appearance,  but  beyond  this 
stage  it  was  not  followed.  The  conjugating  parasites  produced  large 
segmenting  forms  with  16-20  spores. 

The  extent  and  significance  of  this  form  of  conjugation  it  is  difficult 
to  determine.  In  the  cases  in  which  it  can  be  profitably  studied,  para- 
sites are  usually  very  abundant,  and  in  most  cases  few  indications  of 
the  process  can  be  detected.  It  is,  therefore,  probably  not  essential  to 
sporulation,  but  when  parasites  are  scanty  the  chances  of  finding 
typical  examples  of  conjugating  pairs  are  greatly  reduced,  and  the 
peripheral  blood  may  not  be  a  complete  index  of  the  processes  in  the 
internal  viscera.  The  large  size  of  the  sporulating  forms  developed 
from  conjugating  pairs  suggests  that  this  process  is  intended  to  espe- 
cially favor  the  multiplication  of  the  species  in  the  human  host.  It 
seems    probable    that   conjugation  ocours  in  the   first  generations  of 


PLATE    XIV. 


Conjugating  Cycle  of  Tertian  Malarial   Parasite. 


Fig.  I.     Single  compact  body  with  double  chromatin  masses. 

Fig.  2.     Conjugating  rings  of  unequal  size. 

Fig.  3.      Double  infection  with  a  coarse  ring,  double  chromatin  granules,  and  a  thin  ring  form. 

Figs.  4,  5.     Early  stages  of  conjugation  of  a  thin  ring  and  a  compact  body. 

Fig.  6.     Early  ameboid  figures  of  conjugating  rings. 

Fig.  7.     Double  nuclei  in  ameboid  parasite. 

Fig.  8.     Union  of  nuclei,  and  subsidence  of  ameboid  motion  in  older  conjugating  parasites. 

Figs.  9,  10.   Stages  of  union  of  bodies  and  of  three  chromatin  masses,  of  two  conjugating  parasites. 

Fig.  II.     Complete  union  of  bodies  and  nuclei. 

Figs.  12,  15.     Comparative  sizes  of  full-grown  forms  developed  with  and  without  conjugation. 


PARASITES  IN  THE  CIRCULATION.  401 

the  infection  and  becomes  less  frequent  as  the  disease  progresses,  the 
infection  in  the  iiuman  host  thereby  tending  to  limit  itself. 

Several  sources  of  error  in  the  interpretation  of  these  appearances 
have  to  be  considered.  The  presence  of  two  masses  of  chromatin  has 
been  noted  in  single  young  parasites.  Yet  the  existence  of  the  bodies 
of  two  parasites  can  usually  be  determined  with  certainty,  while  some 
conjugating  forms  contain  three  large  masses  of  chromatin  granules,  i. 
e.,  when  one  of  the  conjugating  forms  supplies  an  extra  granule.  The 
conjugating  forms  must,  therefore,  be  identified  from  the  presence  of 
the  bodies  as  well  as  the  chromatin  masses  of  two  parasites. 

The  death  and  extrusion  of  one,  or,  as  suggested  by  Thayer,  of  both 
of  the  twin  parasites  cannot  account  for  the  absence  of  older  twinned 
forms,  since  no  traces  of  such  extrusion  were  encountered.  Twin 
parasites  sometimes  proceed  to  full  development  without  conjugating, 
but  this  event  is  comparatively  rare. 

The  existence  of  these  three  types  of  full-grown  tertian  parasites 
naturally  suggests  that  the  single  compact  form  develops  into  the 
microgametocyte  or  male  flagellating  body,  the  single  ring-shaped  form 
developing  into  the  macrogametocyte  or  female  form,  and  the  conju- 
gating form  into  the  sporulating  body. 

V.    The  Occurrence  of  Parasites  in  the  Circulation. 

In  all  well-marked  initial  attacks  of  malarial  fever  the  parasite  can 
be  found  in  the  blood  if  examined  tvithin  18  hours  after  the  chill.  The 
writer  found  this  rule  to  hold  even  in  patients  who  were  taking  large 
doses  of  quinine,  but  in  one  case  examined  24  hours  after  the  chill 
parasites  could  not  be  found  during  a  search  of  two  hours  through 
stained  specimens. 

In  the  great  majority  of  ciuchonized  cases  of  acute  estivo-autumnal 
fever,  parasites  can  be  found  within  a  week  after  the  beginning  of  the 
paroxysm,  while  crescents  may  persist  for  two  or  three  weeks  or  more. 
In  cases  treated  by  quinine  the  writer  found  the  ameboid  parasites  to 
largely  disappear  from  the  blood  on  the  third  day.  If  no  crescents 
appear,  the  blood  then  becomes  entirely  free  of  parasites,  but  usually 
crescents  enter  the  circulation  on  or  after  the  fourth  day  and  the  ex- 
amination of  the  blood  still  continues  positive. 

On  the  other  hand,  with  very  mild  or  with  cinchonized  cases  a  prolonged 
search  is  sometimes  required  for  the  detection  of  parasites. 

In  a  few  relapses  of  estivo-autumnal  infection,  examined  during  the 
chill,  the  writer  had  to  search  35-50  minutes  before  discovering  a  sin- 
gle parasite,  and  in  several  other  cases  only  young  crescents  could  be 
found,  while  if  the  examination  was  delayed  for  l<S-24  hours,  it  was 
often  necessary  to  search  for  two  hours  or  more.  With  Nocht's  stain 
this  labor  would  probably  have  been  reduced. 

In  cases  that  have  not  taken  quinine,  the  parasites  are  usually  so  abun- 
dant in  well-marked  infections  that  no  difficulty  whatever  is  expanenced  in 
determining  their  presence. 
26 


402  MALARIA. 

Yet  the  well-known  tendency  of  the  estivo-autumnal  parasite  to  re- 
tire from  the  peripheral  blood  during  the  sporulating  stage  may  leave 
the  finger  blood  comparatively  free  from  organisms  at  certain  periods 
of  the  attack.  In  the  tropics,  v.  d.  Scheer  noted  that  if  the  blood 
is  examined  during  the  sporulating  stage  no  parasites  may  be  found, 
and  that  they  may  appear,  in  scanty  numbers  only,  after  some  hours' 
growth.  Marchiafava  and  Bignami  also  emphasize  the  fact  that  a  neg- 
ative result  may  frequently  be  obtained  at  the  beginning  of  an  attack. 
Likewise  in  mild  tertian  infections  initial  paroxysms  occur  in  which 
very  few  parasites  are  present  in  the  blood,  and  in  some  instances  they 
have  been  reported  as  absent  altogether.  The  same  fact  has  been  ob- 
served in  connection  with  experimental  infections. 

Nevertheless,  the  writer  believes  that  in  acute  malarial  fever,  even 
when  quinine  has  been  administered,  parasites  can  always  be  found,  if 
the  blood  is  examined  with  care  and  j^ersistence  within  IS-^I/.  hours  after 
the  chill. 

In  the  majority  of  treated  cases  the  usual  phases  of  development  of 
the  parasite  may  be  found  in  diminishing  numbers. 

Although  Golgi  holds  that  the  number  of  parasites  in  the  periph- 
eral blood  is  no  reliable  indication  of  their  total  numbers  in  the  body, 
yet  the  severer  cases  nearly  always  show  the  larger  numbers,  while  in 
mild  cases  parasites  may  be  very  scarce. 

In  conditions  of  coma  the  blood  may  contain  either  rings  or  crescents, 
or  both,  or  tertian  parasites.  When  coma  arises  in  the  course  of  the 
active  sporulating  cycle,  it  is  almost  invariably  fatal,  and  the  presence 
of  many  ameboid  parasites  in  the  blood  of  such  cases  is  an  extremely 
unfavorable  sign.  In  most  cases  of  malarial  coma,  especially  those  of 
very  abrupt  onset,  or  with  symptoms  of  meningitis  or  of  localized  cor- 
tical irritation,  crescents  only  are  found  in  the  blood  and  recovery 
usually  follows. 

In  some  cases  of  coma  the  roriter  had  to  search  one  and  two  hours  be- 
fore finding  a  single  parasite,  and  has  encountered  some  cases  of  coma 
and  convulsions,  in  subjects  believed  to  be  suffering  from  malaria,  in 
which  no  parasites  could  be  found  in  the  blood. 

The  numbers  of  parasites  to  be  found  in  the  blood  when  they  are 
extensively  massed  in  the  gastro-intestiual  mucous  membrane,  heart- 
muscle,  brain,  etc.,  has  usually  been  considerable.  Yet  the  writer  en- 
countered a  few  cases  of  acute  estivo-autumnal  infection  marked  by 
violent  hematemesis,  in  which  very  few  parasites  were  discoverable  in 
the  blood.  In  one  case  of  malarial  hematemesis  no  parasites  could  be 
found  during  the  first  three  days  of  the  paroxysm,  but  on  the  fourth  day 
numerous  young  crescents  appeared. 

Fatal  Malaria  Without  Parasites  in  the  Peripheral  Blood. — The  ques- 
tion whether  fatal  malaria  exists  without  the  presence  of  demonstrable 
parasites  in  the  blood  has  not  yet  reached  complete  solution.  There  can 
can  be  no  doubt,  however,  that  in  acute  paroxysms,  fatal  on  the  fourth  or 
fifth  day,  or  later,  the  energetic  use  of  quinine  may  rid  the  blood  of  all 
ameboid  bodies,  although  the  patient  dies  from  the  attack.     When  the 


TYPHOID  FEVER  AND  MALARIA.  403 

blood  is  not  examined  until  the  third  day  of  such  attacks  the  result 
may  be  negative. 

Marchiafava  and  Bignami  have  described  peculiar  fatal  cases  of 
estivo-autumnal  infection  occurring  in  debilitated  subjects,  during  very 
hot  weather,  in  which  few  or  no  parasites  were  found  in  the  blood  and 
very  scanty  deposits  of  pigment  were  present  in  the  viscera.  The 
writer  has  reported  a  similar  case,  in  which,  however,  quinine  had 
been  administered  for  some  days  before  the  examination  of  the  blood. 
In  spite  of  these  apparent  exceptions  to  the  rule,  the  writer  believes, 
with  Marchiafava  and  Bignami,  that  fatal  acute  malaria  does  not  exist 
without  the  presence  of  parasites  in  the  blood,  at  least,  at  some  time  during 
the  paroxysm . 

Remittent  Malarial  Fever. — In  remittent  malarial  fever,  per- 
sisting longer  than  seven  days,  the  writer,  in  30  selected  cases,  found 
only  estivo-autumnal  rings  in  8,  crescents  alone  in  11,  both  rings  and 
crescents  in  1,  tertian  parasites  alone  in  1,  double  infection  in  1,  and 
no  parasites  in  8.  Initial  estivo-autumnal  attacks  often  begin  with 
remittent  pyrexia,  and  some  relapses  may  show  a  temperature  which 
requires  three  days  to  reach  its  acme  and  three  or  four  to  decline. 
These  cases  do  not  properly  fall  in  the  class  of  remittent  malarial  fever. 

In  chronic  malaria,  organisms,  principally  crescents,  are  usually  to 
be  found  in  the  blood  when  there  is  fever,  but  are  commonly  absent 
during  afebrile  periods.  In  one  case  the  writer  found  crescents  in  the 
blood  four  weeks  after  the  last  chill,  quinine  having  been  constantly 
administered. 

Long  after  parasites  have  disappeared,  scanty  pigmented  leucocytes 
may  be  encountered  in  the  blood,  but  the  situations  in  which  their  dis- 
covery proves  of  value  in  diagnosis  are  comparatively  rare.  Their  de- 
tection is  more  often  of  value  in  cinchonized  cases  of  acute  fever,  in  which 
parasites  have  disappeared.  Pigmented  leucocytes  are  most  abundant 
shortly  after  the  chill  in  relapses  of  well-established  estivo-autumnal 
infection. 

Since  Marchiafava  and  Bignami  admit  that  in  chronic  malaria 
properly  treated,  mild  paroxysms  may  fail  to  reduce  the  number  of 
red  cells,  and  since  quinine  may  reduce  or  destroy  the  scanty  number 
of  parasites  ordinarily  thrown  into  the  peripheral  blood,  it  is  necessary 
to  admit  that  paroxysms  may  occur  in  chronic  malaria  icithout  diminution 
of  red  cells  and  without  parasites  in  the  blood. 

Yet  such  cases  must  be  excessively  rare  and  by  no  means  open  the 
door  to  the  indiscriminate  diagnosis  of  malaria  in  obscure  fibricula 
without  anemia  or  parasites  in  the  blood.     (See  p.  405.) 

Typhoid  Fever  and  Malaria. 

The  effect  of  intercurrent  typhoid  infection  upon  the  blood  in  malaria 
is  very  distinct.  The  concentration  which  results  in  typhoid  fever 
becomes  at  once  apparent,  the  blood  drop  appears  distinctly  less  fluid, 
and  the  Hb  and  proportion  of  red  cells  rise. 


404  3IA  LABIA. 

During  the  first  week  of  the  disease  sporulation  of  parasites  fre- 
quently continues  and  organisms  may  be  found  in  the  blood  as  usual. 
Illustrations  of  this  coincidence  of  active  malaria  in  the  first  week  of 
typhoid  fever  are  rather  numerous  in  recent  literature.  Aftei'  the  first 
week,  ivhen  the  typhoid  fever  has  become  fully  established,  active  sporulation 
of  malarial  jMrasites  is  extremely  rare. 

Until  recently  there  was  apparently  but  one  case,  reported  by  W.  Gilman 
Thompson,  in  which  active  sporulation  of  the  malarial  parasite  was  shown 
to  have  occurred  at  the  height  of  the  typhoid  infection. 

Of  many  others,  collected  by  Lyon,  most  prove  to  be  examples  of  mala- 
rial paroxysms  occurring  in  the  first  few  days  of,  or  during  convalescence  from 
typhoid  fever.  So  rare  is  the  coincidence  of  parasites  in  the  blood  during 
the  course  of  typhoid  fever  that  neither  Marchiafava,  Bignami,  Bacelli, 
Dock,  or  many  others,  have  ever  seen  a  single  case.  In  159  cases  of  typhoid 
fever,  nearly  all  occurring  in  actively  malarious  subjects,  at  Montauk,  the 
writer  could  find  no  instance  in  which  parasites  were  present  in  the  blood 
during  the  second  to  the  fourth  weeks  of  the  disease,  although  several  early 
or  convalescent  cases  suffered  active  malarial  attacks  with  parasites,  always 
tertian,  in  the  blood.  Cases  of  quartan  infection  associated  with  typhoid 
fever  are  reported  by  Thayer  and  by  Craig. 

VI.    The  Malarial  Anemia. 

There  are  few  conditions  which  lead  so  rapidly  to  such  extreme 
oligocythemia  as  does  acute  malarial  infection.  Kelsch,  who  in  1875 
contributed  an  exhaustive  study  of  malarial  anemia,  found  that  an  acute 
initial  attack  lasting  three  weeks  might  reduce  the  red  cells  to  1  mil- 
lion or  even  to  500,000.  In  robust  subjects  suffering  initial  attacks 
the  loss  on  the  first  day  sometimes  reached  1  million  red  cells,  or  dur- 
ing the  first  four  days,  2  millions.  Dionisi  observed  a  reduction  of 
500,000  cells  in  12  hours.  In  relapses  the  seizure  did  not  cause  so 
great  a  loss  of  cells  as  in  first  attacks.  In  prolonged  cases,  it  was 
often  possible  to  distinguish  three  periods  in  the  progress  of  the 
anemia.  (1)  During  the  first  three  to  four  days  the  loss  of  red  cells 
was  very  rapid.  (1|^  millions  to  2  millions.)  (2)  During  the  afebrile 
interval  and  during  the  relapse  the  fall  was  continuous  but  much  less 
rapid.  The  minimum  of  red  cells  varied  with  the  character  of  the  in- 
fection, being  lower  with  estivo-autumnal  cases,  frequently  falling  below 
2  millions,  seldom  below  1  million.  (3)  When  the  patient  became  very 
anemic,  relapses  reduced  the  red  cells  very  much  less  than  before,  but 
the  active  regeneration  of  cells  caused  their  numbers  to  oscillate.  So 
energetic  may  this  reproduction  of  cells  become  that  even  an  increase, 
instead  of  decrease,  may  be  observed  directly  after  an  attack  in  anemic 
.subjects. 

Initial  attacks  of  pernicious  type  cause  very  marked  loss  of  cells,  but 
in  relapsing  pernicious  cases,  with  severe  established  anemia,  it  is  not 
uncommon  to  find  the  severest  general  symptoms  of  the  paroxysm  un- 
accompanied by  demonstrable  loss  of  red  cells. 

Marchiafava  and  Bignami  find  that  there  may  be  destruction  of  red 
cells,  without  fever,  in  larval  malaria. 


THE  MALARIAL  ANEMIA.  405 

In  chronic  malaria,  the  prolonged  infection,  poor  treatment,  and  bad 
hygiene,  commonly  reduce  the  red  cells  to  1-2  millions,  but  some  ex- 
treme cases  show  below  1  million,  Kelsch  having  one  case  which  gave 
only  583,000.  On  the  other  hand,  in  favorable  subjects,  when  attacks 
occur  at  intervals  of  one  month  or  longer,  and  are  promptly  stopped 
by  quinine,  there  may  be  no  reduction  of  red  cells.  (Marchiafava, 
Bignami.)  The  writer  can  find  no  evidence  on  which  to  extend  this 
exception  to  the  Hb  as  well. 

In  afebrile  periods,  both  between  relapses  and  after  subsidence  of 
the  infection,  the  anemia  may  still  progress.  In  fact  the  writer  found 
this  further  progress  of  post-febrile  anemia  to  be  the  rule  in  all  very 
severe  cases,  and  sometimes  it  proved  fatal.  Dionisi  observed  a  fall 
from  3.2  to  2.3  millions  of  red  cells  during  the  first  six  days  of 
apyrexia,  in  spite  of  the  use  of  iron.  The  regeneration  of  the  blood 
after  benign  tertian  infections  usually  begins  at  once,  but  after  all  per- 
nicious attacks  both  the  response  to  iron  and  the  progress  of  regenera- 
tion are  slower. 

Morphology  of  Red  Cells. — In  cases  of  moderate  severity  the  usual 
changes  in  the  red  cells  of  secondary  anemia  are  present.  Even  in  the 
early  stages  of  anemia,  polychromasia  and  granular  degeneration  of  red 
cells  are  sometimes  to  be  noted,  while  these  changes  increase  steadily 
as  the  anemia  progresses. 

The  grave  post-malarial  anemias  present  some  very  interesting  forms. 
Marchiafava  and  Bignami  describe  three  types,  based  upon  the  changes 
in  blood  and  marrow  : 

1.  The  red  cells  exhibit  the  characters  of  grave  secondary  anemia, 
with  extreme  loss  of  Hb,  but  no  nucleated  red  cells  are  present.  The 
marrow  shows  simple  atrophy  of  lymphoid  cells  and  of  clusters  of 
nucleated  red  cells. 

2.  AVith  the  same  condition  of  the  blood  the  usual  number  of  nucle- 
ated red  cells  may  be  found,  and  there  is  moderate  hyperplasia,  of 
physiological  character,  of  the  lymphoid  marrow. 

3.  The  red  cells  exhibit  the  characters  of  progressive  pernicious 
anemia,  with  high  Hb-index  and  with  megalocytes  and  megaloblasts. 
The  marrow  suffers  typical  megaloblastic  degeneration. 

The  writer's  study  of  blood  and  marrow  in  fatal  cases  supports  this 
division  of  post-malarial  anemias.  AVhile  the  ordinary  features  of  grave 
secondary  anemia  were  usually  found,  there  were  in  the  writer's  Mon- 
tauk  series  no  less  than  19  cases  in  which  the  changes  of  the  progres- 
sive pernicious  type  had  been  established  in  a  period  not  longer  than 
ten  weeks.  In  one  of  these  the  parasites  appeared  to  have  been 
massed  principally  in  the  bone  marrow,  where  their  numbers  were 
enormous  and  instances  of  multiple  infection  of  cells  were  excessively 
numerous.  There  can  be  no  doubt  that  the  tendency  of  the  estivo- 
autumnal  parasite  to  be  massed  in  the  bone  marrow,  in  both  ameboid 
(the  writer)  and  crescentic  phases  (Councilman,  Bastianelli,  Bignami), 
and  the  excessive  demands  on  red  cell  production  arising  in  the  dis- 
ease, render  pernicious  malaria  an  extremely  favorable  condition  for 


406  3fALABIA. 

this  disturbance  of  the  structure  of  the  marrow  and  the  development 
of  specific  megaloblastic  changes. 

In  nearly  all  cases  of  grave  malarial  anemia  polychromasia  is  a 
marked  feature,  and  granular  degeneration  becomes  so  prominent  that 
Plehn  and  others  have  even  described  as  a  peculiar  form  of  the  para- 
site those  collections  of  bluish  staining  granules  which  appear  in  many 
badly  degenerated  cells.  This  form  of  degeneration  was  most  pro- 
nounced in  a  fatal  case  of  benign  tertian  infection  reported  by  the 
writer,  in  which  there  was  also  a  remarkable  grade  of  hydremia,  and, 
in  the  kidneys,  the  lesions  of  hemoglobinuric  fever. 

Besides  the  lesions  referable  to  anemia,  or  to  the  toxemia  of  paludism, 
the  infected  red  cells  suffer  a  peculiar  series  of  changes  resulting  from 
the  presence  of  the  parasite.  Changes  in  the  size  of  the  cell  are 
nearly  constant.  The  tertian  parasite,  almost  from  the  first,  causes 
swelling  of  the  cell  and  progressive  loss  of  hemoglobin,  as  indicated 
by  increasing  pallor.  When  harboring  two  or  three  large  tertian 
parasites  the  red  cell  may  become  enormously  distended. 

When  infected  by  the  quartan  or  any  form  of  estivo-autumnal  ameba, 
the  red  cell  usually  shrinks  and  takes  on  a  peculiar  opaque  "  brassy  " 
color.  This  change  begins  at  the  moment  of  infection  by  the  young 
ring  and  becomes  more  marked  with  the  growth  of  tlie  parasite. 
Marchiafava  and  Bignami  suggest  for  tliis  condition  tlie  appropriate 
term  "  erythropyknosis."  These  authors  believed  that  the  pyknosis 
results  in  the  death  of  both  cell  and  parasite. 

In  many  cells  infected  by  any  form  of  parasite,  especially  the  estivo- 
autumnal,  the  hemoglobin  collects  in  a  dense  layer  about  the  parasite, 
and  achromatic  clefts  often  form  in  the  red  cell.    (Plate  XIIL,  Fig.  13.) 

Fragmentation  of  the  red  cell  is  a  rather  infrequent  result  of  infec- 
tion by  the  parasite. 

Bignami  has  described  an  increased  cohesiveness  of  the  infected  red 
cells  in  estiv^o-autumnal  malaria,  and  explains  thereby  the  tendency  of 
infected  cells  to  gather  in  small  visceral  capillaries. 

Pathogenesis  of  Malarial  Anemia. — In  the  pathogenesis  of  malarial 
anemia  it  is  necessary  to  consider  the  action  of  several  factors.  Each 
infecting  parasite  probably  destroys  more  or  less  completely  the  har- 
boring cell,  and  a  certain  part  of  the  loss  of  red  cells  must  be  referred 
to  this  source.  Yet  Dionisi  has  shown  that  there  is  no  very  close  re- 
lation between  the  number  of  parasites  present  in  peripheral  blood 
and  the  destruction  of  red  cells  which  results  from  a  paroxysm. 

Moreover,  the  plasmodium  does  not  immediately  enter  the  cell  but  re- 
mains for  a  time  merely  attached  to  its  surface,  and  since  quinine  may 
cause  these  extra -globular  parasites  to  abandon  the  corpuscle,  as  de- 
scribed by  Marchiafava  and  Bignami,  it  is  probable  that  in  many 
paroxysms,  properly  treated,  the  destruction  of  cells  resulting  from 
direct  consumption  by  parasites  is  very  slight. 

Many  facts  indicate  that  the  post-critical  anemia  is  principally  refer- 
able to  globulicidal  action  of  the  serum,  dependent  upon  the  presence 
of  a  malarial  toxine.     Some  of  these  facts  are,  the  disproportion  between 


THE  LEUCOGYTOSIS  OF  MALARIA.  407 

the  anemia  and  the  number  of  parasites  present ;  the  steady  diminution 
in  the  loss  of  cells  in  the  second  and  third,  as  compared  with  the  first 
paroxysm  ;  the  further  progress  of  anemia  in  many  cases  after  parasites 
have  disappeared  from  the  blood  (Dionisi,  the  writer)  or  during  inter- 
vals between  paroxysms  (Kelsch) ;  the  occurrence  of  hemoglobin  uric 
malarial  fever,  and  the  increased  resistance  of  cells  demonstrated  by 
Viola  during  the  progress  of  malarial  infection.  The  writer  has 
pointed  out  at  some  length  that  the  chief  bulk  of  pigment  deposited  in 
viscera  is  derived  from  the  globulicidal  action  of  the  plasma  and  not 
from  the  vegetative  functions  of  the  parasite. 

Increased  production  of  red  cells  greatly  alters  the  progress  of  malarial 
anemia,  being  partly  accountable  for  the  smaller  losses  observed  after 
secondary  paroxysms,  and  preserving  intact  or  even  increasing  the 
numbers  of  cells  after  paroxysms  in  very  anemic  individuals. 

VII.     The  Leucocytosis  of  Malaria. 

Most  observers  have  found  very  little  change  in  the  numbers  of  leu- 
cocytes in  the  finger  blood  during  acute  malarial  attacks  of  average 
severity.  This  absence  of  leucocytosis  with  a  rapidly  rising  tempera- 
ture may  be  found  of  considerable  corroborative  value  in  the  diagnosis 
of  malarial  fever. 

A  slight  leucocytosis  at  the  beginning  of  the  paroxysm  has  been 
noted  in  some  cases  by  Kelsch,  Billings,  Vincent,  and  others,  but  the 
numbers  usually  remain  below  10,000,  while  the  percentage  of  poly- 
nuclear  cells  is  increased.  Vincent  finds  that  quinine  tends  to  increase 
the  polynuclear  leucocytes  throughout  the  entire  paroxysm.  With  the 
falling  temperature  and  during  apyrexia  the  leucocytes  are  usually  dis- 
tinctly diminished  (2,000-4,000),  especially  the  polynuclear  forms,  giv- 
ing a  relative  lymphocytosis. 

Except  during  the  3—4  hours  immediately  following  the  chill,  there- 
fore, malarial  blood  usually  shows  a  diminished  number  of  leucocytes, 
and  a  distinct  relative  lymphocytosis.  The  lymphocytes,  small  and 
large,  may  sometimes  become  quite  numerous,  especially  in  well-estab- 
lished cases.  This  fact  accords  with  the  increased  cellular  activity 
of  the  lymphoid  tissues  shown  by  microscopical  examination  of  the 
viscera. 

Marchiafava  and  Bignami  refer  the  lymphocytosis  to  a  specific 
chemotactic  action,  but  it  seems  more  jjrobably  referable  to  simple 
mechanical  factors. 

The  percentage  of  polynuclear  cells  at  the  beginning  of  the  attack  is 
usually  high.  Billings  found  over  80  percent  in  some  cases.  Later 
these  forms  diminish  and  usually  fall  below  60  percent.  In  pernicious 
attacks  Bastianelli  found  below  40  percent  of  polynuclear  cells. 

Bastianelli  refers  the  less  of  polynuclear  leucocytes  to  the  increased 
phagocytic  activity  of  these  cells.  Vincent  noted  a  periodical  decrease 
in  the  number  of  large  mononuclear  cells,  which  he  refers  to  the  same 
process. 


408  3IALARIA. 

In  the  severer  estlvo-autumnal  paroxijsms  many  observers  have  noted 
a  distinct  leucocytosis.  (Kelsch,  Babes  and  Georgliin,  Ziemann,  Burot 
and  Leo-rand.)  Kelsch  found  that  the  leucocytosis  of  pernicious  ma- 
larial attacks  often  consists  in  marked  lymphocytosis,  which  the  writer 
also  has  observed.  Bastianelli  and  Bignami  find  that  in  addition  to 
various  inflammatory  complications,  leucocytosis  in  pernicious  malaria 
may  result  from  rapidly  progressive  anemia.  They  find  it  to  be  of 
frequent  occurrence  in  hemoglobinuric  fever,  and  in  cases  attended 
with  severe  diarrhea.  Plehn,  however,  found  no  leucocytosis  in  most 
of  his  cases  of  hemoglobinuria. 

The  extent  of  the  leucocytosis  varies  between  10,000  and  35,000 
cells,  the  latter  number  having  been  observed  by  Kelsch  shortly  before 
death  in  a  comatose  patient.  Usually  the  leucocytosis  in  pernicious 
attacks  is  much  lower,  and  many  attacks  fail  to  cause  any  distinct  in- 
crease. 

The  presence  of  eosinophile  cells  may  be  noted  in  most  cases  of  mala- 
rial fever,  and  these  cells  are  usually  increased  in  number  during  afebrile 
periods.  Grawitz  rightly  regards  this  feature  as  of  diagnostic  impor- 
tance, as  in  most  diseases  likely  to  be  confused  with  malaria  eosinophile 
cells  are  long  absent  or  scarce.  Bastianelli  and  Bignami  found  that 
eosinophile  cells  diminish  during  the  paroxysm,  and  increase  during 
apyrexia,  while  the  blood  is  regenerating.  In  two  cases  of  pernicious 
malaria,  with  many  parasites,  they  found  many  mononuclear  leucocytes, 
and  a  very  few  eosinophile  myelocytes,  similar  to  those  seen  in  myelog- 
enous leukemia. 

In  chronic  malaria  Kelsch  found  the  leucocytes  usually  subnormal 
in  numbers,  but  in  one  of  33  cases  there  was  transient  leucocytosis. 

Pigmented  leucocytes  are  seen  in  the  majority  of  cases,  most  abun- 
dantly in  the  severe  and  long-established  fevers.  They  are  found  in 
nearly  all  fatal  cases,  but  the  writer  found  them  most  abundant  in  a 
case  which  recovered.  It  appears  that  the  pigmented  leucocytes  are 
more  closely  related  to  the  severity  of  the  antecedent  paroxysms  than 
to  the  extent  of  the  pigment  deposits  in  the  viscera. 

They  are  most  abundant  during  and  shortly  after  the  febrile  period, 
but  are  often  found  in  afebrile  cases  and  after  parasites  have  dis- 
appeared from  the  blood.  The  phagocytic  cells  seen  in  the  blood  in- 
clude mononuclear  and  polynuclear  leucocytes,  and  endothelial  cells. 
The  large  and  smaller  mononuclear  cells  are  most  often  found  to  con- 
tain pigment  or  parasites,  but  in  a  few  cases,  for  reasons  not  clear,  large 
numbers  of  polynuclear  leucocytes  are  found  harboring  rosettes,  other 
forms  of  parasites,  and  pigment.  In  a  few  cases  very  large  endothelial 
macrophages  may  be  found  in  the  blood,  containing  parasites  in  all 
stages  of  degeneration. 

The  objects  englobed  by  phagocytes,  as  seen  in  the  circulation,  in- 
clude :  (1)  Parasites,  free  or  inclosed  in  red  cells.  (2)  Pigment 
elaborated  by  parasites,  usually  in  small  clumps,  sometimes  in  large 
masses.  (3)  Hematoidin  derived  from  the  destruction  of  red  cells. 
(4)  Hemosiderin  derived  from  the  detritus  of  red  cells.     (5)  Intact  or 


BIBLIOGRAPHY.  409 

broken  red  cells.  (6)  Other  leucocytes.  Crystalline  pigment  is  often 
seen  in  leucocytes  in  sections  of  tissues  but  never  in  the  circulating 
blood  during  life. 

The  degenerative  changes  in  phagocytic  leucocytes  mentioned  by 
Bastianelli  and  Bignami,  including  vacuolation  and  diminished  staining 
capacity  of  nuclei,  have  been  noted  by  the  writer  in  many  severe  cases. 
The  number  of  vacuolated  leucocytes  found  in  the  blood  is  consider- 
able and  sometimes  very  large.  Fatty  degeneration  the  writer  has 
been  unable  to  demonstrate. 

From  a  comparison  of  the  phenomena  of  phagocytosis  in  the  circu- 
lating blood  Avith  those  seen  in  the  viscera  of  fatal  cases,  it  is  evident 
that  the  phagocytic  function  of  the  leucocytes  in  malaria  is  very  sub- 
ordinate to  that  of  the  visceral  phagocytes  in  all  but  a  few  exceptional 
cases. 

Bibliography. 

The  literature  on  malaria  has  become  so  extensive  that  it  has  been 
thought  best  to  omit  from  the  present  list  any  references  except  to 
important  original  studies,  and  to  a  few  recent  contributions. 

A  most  serviceable  bibliography,  alphabetically  arranged,  will  be 
found  in  Mannaberg's  monograph.  Die  Malaria  KrankheUen,  in  Noth- 
nageVs  Spec.  Path.,  II.  Bd.,  II.  Th.      Wien,  A.  Holder,  1899. 

BarbaccPs  lists,  Cent.  f.  Path.,  1899,  p.  64,  are  also  very  complete 
and  more  recent. 

Many  articles  up  to  1895  will  be  found  more  accessible  to  Ameri- 
can readers  in  the  references  given  by  Thayer  and  Hewetson,  The  Ma- 
larial Fevers  of  Baltimore,  Johns  Hopkins  Press,  1895. 

Babes,  Oeorghiu.  Etudes  sur  les  differentes  formes  du  parasite.  Annal.  de  I'lnsti- 
tut  de  pathol.  de  Bucharest,  1890.  Cited  by  Barbacci,  Cent,  fiir  Path.,  1899.  Archiv 
de  med.  nav.,  1893,  Mar. 

Barbacci.     Neuere  Arbeiten  iiber  Malaria,  1892-7,  Cent,  fiir  Path.,  1899,  p.  64. 

Bastianelli,  Bignami.  Studi  siilla  infezione  malarica.  Bull.  d.  E.  Ac.  med.  di  Roma, 
1893,  1894.     Archiv  Ital.  d.  Biol.,  1895,  XXIII.,  III. 

Bignami.  Recherche  suU'anat.  d.  perniciose,  Atti.  d.  R.  Ac.  med.  di  Roma,  1890, 
Vol.  V.  Studi  sull'anat.  patol.  d.  infez.  malar,  cronica,  Atti.  d.  R.  Ac.  Roma,  1893. 
Inoculation  theory  of  malarial  infection,  Lancet,  1898,  II.,  pp.  1461,  1541. 

Bignami,  Bastianelli.     Structure  of  flagellate  bodies.  Lancet,  1898,  II. ,  p.  1620. 

Bignami,  Dionisi.     Le  anemie  postmalarische,  XI.  Internat.  Cong.,  Rome,  1894. 

Billings.     Johns  Hopkins  Bulletin,  1894,  p.  89. 

Burot,  Legrand.     Therapeutique  du  paludisme,  Paris,  Balliere  et  Fils,  1897. 

Celli,  Guarnieri.     Aetiologie  der  Malariainfection,  Fort.  d.  Med.,  1889,  p.  521. 
Councilman.     Fort,  der  Med.,  1888,  Nos.  12-13. 

Craig.     Philad'a  Med.  Jour.,  Vol.  3,  p.  1369. 

Dock.     Pernicious  Malarial  Fever,  Amer.  Jour.  Med.  Sci.,  1894,  Vol.  107,  p.  379. 

Emng.  Results  of  Blood  Examinations  at  Camp  Wickoff.  N.  Y.  Med.  Journ., 
1899,  Vol.  69,  pp.  114-149.     Also,  Jour,  of  Exper.  Med.,  1901.^ 

Futcher,  Lazear.     Johns  Hopkins  Bulletin,  1899,  Vol.  X.,  p.  70. 

Gautier.     Malariastudien  im  Kaucasus,  Zeit.  f.  Hygiene,  1898,  Bd.  28,  p.  439. 

Golgi.  Fort.  d.  Med.,  1886,  No.  17.  Fort.  d.  Med.,  1889,  No.  3.  Ueber  die  rom- 
ischen  Sommer-herbstfieber,  Deut.  med.  Woch.,  1894,  Nos.  13,  14. 

Grassi,  Bignami,  Bastianelli.  Archiv  Ital.  de  Biol.,  1899,  T.  31,  p.  259.  Archiv 
Ital.  de  Biol.,  1899,  T.  32,  p.  46. 

Gra-ssi,  Feletti.     Cent.  f.  Bact.,  1890,  1891,  Nos.  12-16. 

Guarnieri.     Atti.  d.  R.  Accad.  med.  di  Roma,  1887. 

Kelsch.     Archiv  d.  Physiol.,  1870,  p.  490  ;  1875,  p.  690. 


410  MALARIA. 

KeUeh,  Kiener.     Maladies  des  pays  chauds,  Paris,  Balliere  et  Fils,  1889. 

Laveran.     Traite  du  Paludisrae,  Paris,  1898,  Masson  et  Cie. 

Leukowicz.     Cent.  f.  Bact.,  1897,  p.  129. 

Lyon.     Amer.  Jour.  Med.  Sci.,  Vol.  117,  p.  25. 

MacCallum.  On  the  liematozoan  infection  of  birds,  Jour,  of  Exper.  Med.,  1898, 
p.  117. 

Mannaberg.     Die  Malaria  Krankheiten,  Wien,  A.  Holder,  1899. 

Manson.     Lancet,  1896,  Vol.  II.,  p.  1715. 

Marchiafava.  Archiv  Ital.  d.  Biol.,  1895,  p.  cxli.  XL  Internat.  Cong.  Eome,  Vol. 
IL,  p.  225. 

Marchiafava,  Bignami.  Aestivo-autumnal  Malaria  (translation  by  Sydenham,  Soc, 
1894).  IJeber  die  Varietaten  der  Malariaparasiten,  Deut.  med.  Woch.,  1892,  Nos. 
51-52.     Also  20th  Century  Practice,  1900. 

Marchiafava,  Celli.  Bull.  d.  R.  Ac.  di  Eoma,  1887.  Atti.  d.  R.  Ac.  di  Roma, 
1887,  Vol.  HI.  Archiv  Ital.  de  Biol.,  1888,  Fasc.  III.  Atti.  R.  Acad.  med.  Roma, 
1890-91. 

Marchoux.     Le  paludisrae  au  S^n^gal,  Annal.  de  I'lnstitut  Pasteur,  1897,  No.  8. 

Marshall.     Lancet,  1896,  Vol.  II. 

Nocht.     Zur  Fiirbung  der  Malariaparasiten,  Cent.  f.  Bact.,  1898,  p.  839  ;  1899,  p.  17. 

Okintschiiz.     Cited  by  Barbacci. 

Plehn.  Schwarzwasserfieber  an  der  Afrikanische  Westkiiste,  Deut.  med.  Woch., 
1895,  Nos.  25-28.  Beitrage  zur  Kenntniss  der  trop.  Malaria,  Berlin,  Hirschwald, 
1896. 

Bomanowsky.     St.  Petersburg  med.  Woch.,  1891,  Nos.  34,  35. 

Boss.  Du  role  des  moustiques  dans  le  paludisme,  Annal.  de  I'lnstitut  Pasteur, 
1899,  No.  2,  pp.  251,  289.  Brit.  Med.  Jour.,  1897,  IL,  pp.  1179,  1786  ;  1898,  L,  pp. 
550,  1575,  1607. 

Sacharoff.  Recherch.  sur  le  parasite  des  fievres  palustres  irr^g.,  Annal.  de  I'lnstitut 
Pasteur,  1891,  No.  5.  Cited  by  Barbacci  (1893).  Ueber  der  Einfluss  der  Klilte  auf, 
*  *  *  der  Malaria -parasiten.  Cent.  f.  Bact.,  1894,  Nos.  5,  6.  Ueber  die  selbstandige 
Bewegung  der  Chrosmosomen  bei  Malariaparasiten,  Cent.  f.  Bact.,  1895,  Nos.  12,  13. 

Smith.     Etiology  of  Texas  Cattle  Fever,  N.  Y.  Med.  Jour.,  1899,  Vol.  LXX.,  p.  47. 

Solly,  Carter.     Presbyterian  Hospital  Report,  1899. 

Thayer,  Hewetson.  Malarial  Fevers  of  Baltimore,  Baltimore,  Johns  Hopkins  Press, 
1895. 

Thompson.     Trans.  Assoc.  Amer.  Phys.,  1894. 

Van  der  Scheer.     Ueber  tropische  Malaria,  Virchow's  Archiv,  1895,  Bd.  139. 

Vincent.     Annal.  de  I'lnstitut  Pasteur,  1897,  No.  12. 

Ziemann.  Ueber  Malaria  u.  andere  Blutparasiten,  Jena,  6.  Fischer,  1898.  Also 
Cent.  f.  Bact.,  1897,  Bd.  XXL,  Nos.  17,  18.     Cent.  f.  Bact.,  1896,  p.  653. 


CHAPTER    XXIV. 
RELAPSING   FEVER. 

Morphology  of  the  Parasite. — The  parasite  of  relapsing  fever, 
discovered  in  the  fresh  blood  by  Obermeier  in  1873,  is  a  spirilkim 
about  16  to  40  n  in  length,  and  is  subject  to  considerable  varia- 
tions in  size.  It  is  very  thin,  sharply  contoured,  structureless, 
and  resembles  a  curled  fibrin-fibril.  Soudakewitch  described  irregu- 
larly contoured  spirilla  and  some  with  a  granular  swelling  at  one  end 
which  he  regarded  as  a  spore.  Several  parasites  may  be  twisted  to- 
gether, and  occasionally  considerable  numbers  are  found  in  a  granular 
looking  mass.  These  nests  are  supposed  to  form  in  stagnating  blood. 
Orth  and  Poufick  failed  to  find  the  spirilla  in  the  blood  of  the  cadaver, 
but  in  the  fresh  blood  movements  may  be  observed  for  two  to  eight 
hours.  Sometimes  they  are  motionless.  (Engel.)  Albrecht  saw  a  con- 
siderable increase  in  their  numbers  in  specimens  that  had  stood  six 
hours,   and    in    one    of    Lachman's 

cases  a  marked  increase  appeared  to  Fig.  25. 

occur  in  the  cadaver.  ^      ~~~ 

Bodies  of  Uncertain  Char- 
acter Described  in  the  Blood 
OF  Recurrent  Fever. — There  has 
always  existed  a  belief  that  forms  of 
the  parasite  other  than  the  spirillum 
must  occur  in  the  blood,  and  various 
bodies  believed  to  represent  develop- 
mental stages  of  the  parasite  have 
been  described.  ^  S  / 

Sarnow  and  v.  Jaksch  found,  dur- 
ing the  afebrile  interval,  spore-like  ' 
bodies   resembling  cocci  which   be- 
came very  numerous  before  the  chill.     ^   Spmiium  ..r  ( n.n  m,  i.  -■  in  luiman  i.iood. 

.'  ,  Carbolic     fuchsiue.      MagiuheU    1,000    diam. 

V.  Jaksch  claimed  to  have  seen  these     (From  slatek  &  spitta's  Atlas.) 
bodies  develop  into  typical  spirilla. 

Larger  protoplasmic  masses  of  varying  structure  were  described  by 
Obermeier,  Ponfick,  Blisener,  Litteu,  Albrecht,  and  others.  Hei- 
denreich  described  them  minutely,  as  compact,  or  vacuolated,  variously 
subdivided,  of  different  sizes,  containing  granules,  fat  droplets,  or  red 
blood  cells.  Sacharoff  also  described  such  masses,  finding  them  most 
abundant  in  the  afebrile  period,  some  being  20  times  the  diameter  of 
a  red  cell.  He  claimed  to  have  observed  the  formation  of  flagella  and 
their  separation  from  the  mass.     Some  of  these  flagella  entered  red 


412  RELAPSING  FEVER. 

cells  and  developed  into  similar  large  protoplasmic  masses,  after  the 
manner  of  the  malarial  crescent.  From  the  nucleus  of  the  parent 
mass  other  slender  flagella  were  protruded,  which  on  becoming  free, 
circulated  in  the  plasma  as  the  spirilla.  Heidenreich  regarded  these 
observations  of  Saccharoff  as  of  great  importance  in  the  biological  study 
of  the  parasite,  but  they  do  not  appear  to  have  been  followed  up. 

Method  of  Demonstration. — In  dry  specimens  of  blood  the  spirilla 
stain  well  with  aniline  dyes,  and  Karlinski  succeeded  in  demonstrating 
flagella  with  some  individuals.  Concentrated  solution  of  methylene- 
blue  stains  all  spirilla  in  2-5  minutes. 

Examination  in  the  fresh  condition  yields  interesting  information  re- 
garding the  movements  of  the  spirilla,  and  should  be  employed  to  dem- 
onstrate their  motility,  but  not  for  the  determination  of  their  presence 
in  doubtful  cases. 

Occurrence  in  the  Blood. — Heidenreich  found  a  few  spirilla  in 
the  blood  24  hours  before  the  chill,  but  most  observers  have  failed  to 
find  any  at  this  time. 

With  the  rise  in  temperature  the  parasites  are  usually  to  be  found  in 
small  numbers,  one  parasite  in  10-20  fields  of  the  microscope.  (Moc- 
zutkowsky.)  They  are  always  to  be  found  on  the  second  day  (Blisener), 
and  thereafter  rapidly  increase,  often  to  enormous  numbers  (e.  g.,  20-30 
in  one  field).  Yet  Engel  claimed  that  even  during  high  fever  the  para- 
sites can  not  always  be  found  in  the  blood.  During  defervescence  the 
numbers  steadily  diminish,  and  in  the  afebrile  periods  may  entirely 
disappear,  but  Naunyn,  Birch-Hirschfeld,  Litten,  and  Unterberger, 
found  an  occasional  parasite  at  varying  intervals  during  the  afebrile 
period. 

With  each  succeeding  paroxysm  the  spirilla  are  apt  to  appear  in  in- 
creasing numbers,  but  there  is  no  strict  parallel  between  their  abun- 
dance in  the  blood  and  the  height  of  the  temperature,  while  it  has 
been  shown  that  their  numbers  vary  both  from  day  to  day,  and  in 
different  parts  of  the  circulation. 

Artificial  Cultivation. — Heidenreich  kept  the  spirilla  alive  for  180 
days  in  defibrinated  blood.  The  single  cultures  were  preserved  longest 
at  a  temperature  of  18-21°  C,  but  at  febrile  temperature  they  soon 
became  motionless.  They  were  very  sensitive  to  oxygen,  CO2,  saliva, 
ascitic  fluid,  urine,  and  to  moderate  variations  in  the  quantity  of  salts 
in  the  fluid.  Heidenreich  and  Kannenberg  believe  this  sensitiveness 
to  slight  changes  in  the  temperature  and  osmotic  tension  of  the  sur- 
rounding medium  explains  the  short  life  of  the  parasite  in  the  human 
body,  but  Moczutkowsky  found  them  to  resist  a  temperature  of  48°  C. 

Multiplication  in  artificial  media  has  been  successful  only  in  the 
hands  of  Koch,  but  the  method  was  not  fully  described.  Inoculation 
in  monkeys  was  first  successfully  performed  by  Carter  and  Koch,  the 
animals  exhibiting  the  symptoms  of  the  disease  and  their  blood  con- 
taining numerous  spirilla.  Obermeier  and  Engel  had  negative  results 
from  the  injection  of  blood  into  dogs,  rabbits,  and  guinea-pigs.  Moc- 
zutkowsky performed  several  successful  inoculations  in  men.     Very 


SEB  UM  DIA  GNOSIS.  413 

interesting  results  were  obtained  by  Albrecht,  who  kept  in  a  moist 
chamber  specimens  of  blood  drawn  when  the  spirilla  had  temporarily 
disappeared.  After  5-6  days,  in  some  specimens,  the  spirochetse 
appeared  in  large  numbers.  Albrecht  describes  what  he  believes  to  be 
the  intermediate  stage  of  development  of  the  parasite. 

Destruction  of  the  spirilla  in  the  blood  is  accomplished,  according  to 
Wernich,  by  means  of  the  products  elaborated  by  the  parasites  them- 
selves ;  according  to  Heidenreich,  through  the  great  susceptibility  of 
the  germ  to  changes  in  temperature  and  chemical  composition  of  the 
blood ;  according  to  Moczutkowsky,  through  concentration  of  the 
blood,  the  density  of  which,  however,  diminishes  during  the  paroxvsm 
(Trautgott)  ;  and  according  to  MetchnikofF  and  Sudake witch,  by  pha- 
gocytosis. 

The  paralyzant  effects  upon  the  spirilla  of  the  serum  of  patients 
who  have  recovered  from  the  disease  indicate  that  specific  bactericidal 
principles  are  developed  in  the  blood.  (Mamourofsky,  Gabritschew- 
sky.)  Yet  the  studies  of  Soudakiewitch  on  phagocytosis  in  relapsing 
fever  are  among  the  most  important  on  which  the  doctrine  of  phagocy- 
tosis is  founded,  and  have  placed  beyond  doubt  its  importance  in  the 
destruction  of  the  spirillum  of  Obermeier. 

Changes  in  Red  Cells. — Boeckman  reported  that  the  red  cells  sink 
during,  and  for  1—2  days  after,  the  attack,  increasing  somewhat  in  the 
afebrile  periods.  Halla  counted  4.6  million  red  cells  on  the  nineteenth 
day  of  the  illness,  and  found  50  percent  of  Hb  in  a  severe  case. 

Leucocytes, — Laptschinsky,  Heidenreich,  and  Boeckman,  all  noted 
considerable  leucocytosis,  most  marked  just  after  the  crisis.  Lapt- 
schinsky mentioned  the  presence  of  a  very  large  number  of  coarsely 
granular  leucocytes. 

Bilious  Typhoid  Fever  (Griesinger). — In  1854  Griesinger  de- 
scribed under  the  term  typhus  icteroides,  a  disease  which  occurred  in 
epidemic  form  in  Cairo,  and  sporadic  cases  of  which  still  persist  in 
Smyrna.  Moczutkowsky,  Karlinsky,  Heidenreich,  and  others,  fully 
demonstrated  the  nature  of  this  malady  by  finding  in  every  case  large 
numbers  of  the  spirillum  of  Obermeier. 

Serum  Diagnosis. — Gabritschewsky  found  that  when  the  blood  of 
a  patient  who  had  just  recovered  from  relapsing  fever  was  added  to  a 
specimen  of  blood  containing  spirilla  and  kept  in  the  thermostat,  the 
parasites  became  motionless  within  one-half  to  one  hour. 

Loewenthal  applied  this  fact  to  the  diagnosis  of  relapsing  fever  dur- 
ing the  apyretic  interval  when  parasites  are  absent  from  the  blood. 
The  specific  reaction  was  most  marked  immediately  after  the  paroxysm, 
diminished  steadily,  and  sometimes  became  inappreciable,  just  before  the 
next  chill.  In  cases  which  had  successfully  overcome  the  infection  the 
reaction  persisted  longer,  and  Loewenthal  claimed  that  if  it  persisted 
as  late  as  the  seventh  day  in  sufficient  intensity  to  immobilize  the  spir- 
illa in  one  hour,  no  farther  relapses  ever  occurred,  otherwise  relapses 
invariably  followed.  There  are  several  uncertainties  connected  with 
the  work  of  Loewenthal  and  his  claims  require  confirmation. 


414  RELAPSING  FEVEB. 

BiBLIOGEAPHY. 

Kelapsing  Fever. 

Albrecht.     Deut.  Arcliiv  f.  klin.  Med.,  Bd.  29,  p.  77. 

Birch-Hirsckfdd.     Archiv  f.  klin.  Med.,  Bd.  13,  p.  346. 

Blisener.     Diss.  Berlin,  1873. 

Boeckman.     Deut.  Archiv  klin.  Med.,  Bd.  29,  p.  481. 

Carter.     Brit.  Med.  Jour.,  1881,  Oct.  1. 

Encjel.     Berl.  klin.  Woch.,  1873,_p.  409. 

Gabritschewsky.     Annal.  de  I'Institut  Pasteur,  1896,  p.  630. 

Griesinger.     Archiv  f.  physiol.  Heilk.,  1854,  p.  554. 

Heidenreich.     Untersuch.  u.  d.  Parasit.  d.  Euckfallstyphus,  Berlin,  1877. 

V.  Jaksch.     Klin.  Diagnostik. 

Kannenberg.     Charit^-Annalen,  1878,  p.  235. 

Karlinski.     Fort.  d.  Med.,  1891,  p.  456. 

Koch.     Mitt.  a.  d.  kais.  Gesundheitsamte,  Bd.  1,  p.  40. 

Lachman.     Deut.  Archiv  klin.  Med.,  Bd.  27. 

Laptschinsky.     Cent.  f.  med.  Wissen.,  1875,  p.  36. 

Liiten.     Deut.  Archiv  klin.  Med.,  Bd.  13,  p.  155. 

Lowenthal.     Deut.  med.  Woch.,  1897,  p.  560. 

Mamourofsky.     Revue  medicale,  1894,  p.  20. 

Metchnikoff.     Virchow's  Archiv,  Bd.  109,  p.  177. 

Moczutkowsky.     Deut.  Archiv  klin.  Med.,  Bd.  24,  p.  80;  Bd.  30,  p.  165. 

Naunyn.     Berl.  klin.  Woch.,  1874,  p.  81. 

Obermeier.     Cent.  f.  med.  Wissen.,  1873,  No.  10.     Berl.  klin.  Woch.,  1873,  p.  391. 

Orth.     Path,  anat.,  Diagnose. 

Ponfick.     Cent.  f.  med.  Wissen.,  1874,  No.  25. 

Saccharoff.     Cent.  f.  Bact.,  1889,  Bd.  5,  p.  420. 

Sarnow.     Diss.  Leipsic,  1882. 

Soudakiewitch.     Annal.  de  I'Institut  Pasteur,  1891,  p.  545. 

Tmutgott.     Cited  by  Kiliani,  20th  Cent.  Practice,  Vol.  16,  p.  477. 

Unterberger.     Jahrbuch  f.  Kinderheilk.,  Bd.  10. 

Wemich.     Berl.  klin.  Woch.,  1880,  No.  54. 


CHAPTER    XXV. 

MISCELLANEOUS  PARASITIC   DISEASES. 

TRICHINA  SPIRALIS. 

The  relation  of  trichinosis  to  the  blood  is  found  principally  in  the 
extreme  degree  of  eosinophilia  which  marks  the  condition. 

The  red  cells,  in  trichinosis,  do  not  suffer  greatly.  After  recovery 
from  the  disease,  when  the  disturbing  effects  of  fever  are  eliminated,  a 
moderate  grade  of  chlorotic  anemia  is  usually  to  be  noted.  Thayer  re- 
ports 4.3  million  red  cells  and  68  percent  of  Hb  in  a  recent  case.  In 
the  majority  of  active  cases  the  red  cells  are  slightly  or  not  at  all  dimin- 
ished, while  the  effects  of  cyanosis  in  concentrating  the  blood  have 
several  times  been  encountered. 

Leucocytes. — All  cases  have  shown  leucoeytosis,  ranging  from  a 
slight  increase  to  35,700  cells,  recorded  by  Brown.  This  leucoeytosis 
is  usually  in  proportion  to  the  severity  of  the  disease  (Blumer  and 
Neuman),  and  persists  in  moderate  degree  for  weeks  or  months. 

The  leucoeytosis  is  a  natural  accompaniineut  of  the  exudative  myositis 
caused  by  the  parasite.  Brown  observed  a  considerable  deposit  of  oxyphile 
cells  in  the  neighborhood  of  some  of  the  cysts  and  concluded  that  the  trans- 
formation of  neutrophile  cells  occurs  in  the  muscles  and  blood  stream,  a 
view  which  cannot  at  present  be  accepted.  In  Lambert's  and  Brooks'  case 
the  writer  could  find  no  evidence  of  the  transformation  of  neutrophile  into 
eosinophile  granules,  although  some  of  the  eosinophile  granules  were  un- 
usually small.  In  the  muscles  the  writer  found  a  very  scanty  deposit  of 
eosinophile  cells,  the  majority  of  new  cells  being  polynuclear  or  mononu- 
clear leucocytes  or  proliferated  muscle  and  endothelial  cells. 

Eosinophilia. — Although  the  presence  of  marked  eosinophilia  in 
various  forms  of  intestinal  parasites  was  fully  demonstrated  by  Bucklers 
in  1894,  its  occurrence  in  trichinosis  was  not  reported  until  Thayer 
and  Brown,  in  1897,  encountered  a  well-marked  case  at  Johns  Hop- 
kins Hospital.  Since  then  numerous  confirmatory  reports  have  been 
contributed  by  Cabot,  Gwyn,  Atkinson,  Stump,  Blumer,  Neuman, 
Lambert  and  Brooks,  and  others. 

From  these  observations  it  appears  that  trichinosis  is  invariably  ac- 
companied by  marked  eosinophilia.  Yet  while  the  leucoeytosis  is  usu- 
ally in  proportion  to  the  severity  of  the  disease,  the  eosinophilia  bears 
no  such  constant  relation.  One  of  Blumer's  mild  cases  showed  50  per- 
cent of  eosins,  and  a  recovering  case,  reported  by  Brooks,  gave  83  per- 
cent. Proportions  of  40-60  percent  are  usually  found,  but  at  some 
periods  they  may  fall  to  8-10  percent.  As  a  rule,  when  the  neu- 
trophile cells  are  abundant  the  eosinophile  are  scanty,  and  viee  versa. 


416 


MISCELLANEOUS  PARASITIC  DISEASES. 


The  eosinophilia  appears  to  be  very  persistent,  15  percent  of  these 
cells  remaining  after  four  and  one-half  months  in  Stump's  case,  and 
34.7  percent  after  five  months  in  one  of  Brown's  cases. 

The  constancy  and  extent  of  eosinophilia  in  trichinosis  renders  the 
examination  of  the  blood  of  great  value  in  the  diagnosis  of  this  infec- 
tion. It  seems  possible  that  mild  cases  have  been  overlooked  in  the 
past  which  might  have  been  detected  by  this  means. 

Yet  while  the  presence  of  marked  eosinophilia  should  always  sug- 
gest the  possibility  of  trichinosis,  there  is  no  great  pathognomonic  value 

Fig.  26. 


Fig.  27. 


Trichina  spiralis  (magnified),  a,  female  ;  6, 
male ;  c,  embryo.     (FromSAHLi. ) 


Male  bilharzia  with  female  partly  inclosed  in  gyne- 
cophoric  canal.    (LoKTETand  Vialleton.) 


attached  to  the  symptom,  since  equal  grades  of  eosinophilia  have  long 
since  been  shown  to  accompany  a  great  many  other  conditions.  The 
least  that  must  be  required  in  the  diagnosis  is  an  unequivocal  clinical 
course,  in  which  case  the  examination  of  the  blood  is  secondary  co- 
roborative  evidence,  or  the  demonstration  of  eosinophilia  in  the  blood, 
and  trichinae  or  exudative  inflammation  in  the  muscles  (Stump,  Brooks). 


DISTOMA   (BILHARZIA)    HEMATOBIUM. 

This  is  a  nematode  worm,  very  abundant  in  Egypt  and  South  Africa, 
and  occasionally  found  in   the  United  States.     The  male  is  whitish, 


ASCARIS  LUMBRICOIDES. 


417 


7-16  mm.  long;  the  female,  often  found  in  the  gynecophoric  canal 
of  the  male,  is  darker  and  finer  and  reaches  20  mm.  in  length.  These 
worms  inhabit  the  smaller  veins  of  the  portal  system,  where  as  many 
as  300  individuals  have  been  found. 

The  ova,  in  the  encysted  stage,  have  the  shape  of  a  melon  seed, 
1/200  to  1/100  inch  in  length,  with  a  transparent  shell  in  which  the 
ciliated  embryo  may  be  seen.  These  ova  are  deposited  in  the  capillary 
plexuses,  where  they  cause  stasis  and  hemorrhages.  They  are  found 
in  the  wall  of  the  bladder,  rectum,  kidney,  ureter,  and  in  the  lungs, 
but  never  in  the  spleen,  pancreas,  or  stomach.  (Lortet,  Vialleton.) 
Kartulis  found  them  widely  distributed,  occurring  even  in  tumors  of 

Fig.  28. 


Blood  clot  in  urine  showing  ova  of  bilharzia  (slightly  magnified. )     (After  Lortet  and  Vialleton.  ) 

the  bladder  which  frequently  arise  in  these  subjects.  He  could  never 
find  them  in  the  heart's  blood.  The  ova  are  usually  detected,  clin- 
ically, in  the  blood  clots  which  pass  with  the  urine,  where  their 
appearance  is  somewhat  characteristic. 

The  life  history  and  mode  of  infection  have  been  only  partly  traced. 

Severe  grades  of  anemia  sometimes  follow  the  repeated  attacks  of 
cystitis  and  hematuria. 

ASCARIS   LUMBRICOIDES    (OXYURIS)    (TENIA). 

Demme  reports  a  case  of  fatal  anemia  in  a  child,  with  1.65  million 
red  cells,  and  large  masses  of  ascarides  in  the  intestines.  Bucklers 
found  41  percent  of  Hb  in  one  case,  and  in  a  series  of  cases  counted 

27 


418 


MISCELLANEOUS  PARASITIC  DISEASES. 


various  proportions  of  eosinophile  cells,  maximum  12.25  percent.  In 
a  case  of  oxyuris  he  found  16  percent  of  eosins,  while  in  mixed  infec- 
tions of  oxyuris  and  ascaris,  the  proportions  were  somewhat  higher, 
maximum  19.31  percent.  In  cases  of  tenia,  eosinophilia  was  moderate 
or  absent,  the  maximum  being  10.25  percent. 


Fig.  29. 


ANGUILLULA   STERCORALIS    (INTESTINALIS). 

Anguillula  stercoralis  is  a  nematode  worm  which  is  often  associated 
with  anchylostoma.    It  measures  2.2  mm.  in  length,  while  the  embryos 

are  but  .2-.3  mm.  long.  The  ova  develop 
very  rapidly  in  the  intestinal  tract,  and  are 
passed  in  the  stool  only  after  catharsis. 
They  were  believed  by  Normand,  their  dis- 
coverer, and  by  Davaine  and  Perroncito,  to 
be  the  cause  of  a  severe  form  of  diarrhea 
prevalent  in  Cochin  China,  and  often  accom- 
panied by  severe  anemia.  Manson,  how- 
ever, claims  that  they  are  innocuous,  al- 
though Davaine  found  them  present  in  great 
numbers  in  cases  of  anemia. 

Lately  Teissier  reported  the  discovery  of 
numerous  embryos  of  anguillula  in  the 
blood  of  a  case  of  intermittent  fever. 
With  the  expulsion  of  the  worms  from  the 
intestine  the  fever  declined  and  the  embryos 
disappeared  from  the  blood.  Bucklers  re- 
ported 13.5  percent  of  eosinophile  cells  in 
the  blood  of  one  case. 


ANCHYLOSTOMA   DUODENALE. 

This  parasite  is  of  nearly  universal  dis- 
tribution in  tropical  latitudes,  and,  although 
located  in   the    small  intestine,  secures  its 
nourishment   from  the   blood    of  the  host. 
It  much  resembles  the  ordinary  pin  worm 
(oxyuris),  being  cylindrical  in  form,  6  to  11 
by  .4  to  .5  mm.  in  dimensions  (the  females 
are    somewhat    shorter    and    thicker),    and 
being  white  when  alive,  gray  when    dead, 
and  reddish  brown  when  full  of  blood.    The 
head  is  provided  with  four  hooks  by  which 
the   parasite    attaches    itself  firmly  to    the 
mucous  membrane.     The  ova  as  found    in  the  feces  are  similar   in 
general  appearance  to  those  of  bothriocephalus,  but  the  yolk  globules 
are  larger. 

The  extra-corporeal  development  passes  through  several  phases,  infec- 


Anguillula  intestinalis,  female  and 
embryo.    (Golgi  and  Monti.  ) 


ANCHYLOSTOMA  DUODENALE.  419 

tion  occurring  by  the  transfer  of  earth  containing  the  encysted  embryos 
to  the  stomacli  of  the  host.  Leichtenstern  has  sliown  that  anchylos- 
toma  does  not  require  a  second  host  for  the  completion  of  its  cycle  but  may 
pass  from  man  to  man  after  a  short  period  of  extra-corporeal  development. 
Ova  appear  in  the  stools  within  4  to  5  weeks  after  the  ingestion  of  the 
embryos. 

Although  discovered  in  1838  by  Dubini,  its  pathological  importance  was 
first  established  by  Griesinger  who,  in  1854,  showed  it  to  be  the  specific 
agent  in  the  so-called  "  Egyptian  chlorosis."  Later  it  was  identified  as  the 
cause  of  many  forms  of  tropical  anemia,  especially  by  Wucherer  in  Brazil, 
and  Perroncito  in  Italy.  Through  the  studies  of  Grassi,  Cinisella,  and 
others,  anchylostomiasis  became  known  in  Italy  as  the  specific  cause  of  the 
anemia  of  mountaineers,  tunnel  workers,  etc. ,  while  the  discovery  by  Son- 
deregger,  and  others,  of  the  same  parasite  in  the  St.  Gothard  epidemic  called 
general  attention  to  the  subject.  In  Germany  the  anemia  which  had  long 
since  been  described  by  Heise  among  brickmakers  was  placed  in  the  same 
class  from  the  discovery  of  the  anchylostoma  by  Menche,  in  an  epidemic  at 
Cologne.  From  these  sources  the  course  of  infection  was  traced  to  nearly 
all  parts  of  middle  Europe.  Isolated  cases  are  still  occasionally  described 
from  these  regions,  while  the  disease  remains  epidemic  in  many  tropical  re- 
gions.    Only  imported  cases  seem  to  occur  in  the  United  States. 

Mode  of  Infection. — The  chief  source  of  infection  is  by  the  transfer 
of  the  embryos  to  the  mouth  by  dirty  hands.  The  rapid  spread  of  the 
disease  and  its  contagiousness  are  explained  by  the  rapid  development 
of  the  ovum  which,  on  leaving  the  host,  reaches  the  encysted  form, 
capable  of  further  infection,  within  one  or  two  weeks.  (Manson.)  A 
second  mode  of  infection,  pointed  out  by  v.  Schopf  and  demonstrated 
experimentally,  consisis  in  the  inhalation  of  the  encysted  larvae  in 
dust.  In  the  alkaline  fluids  of  the  duodenum  the  chitinous  hull  of  the 
embryo  is  dissolved,  when  the  young  worm  promptly  attaches  itself  to 
the  mucosa.  Only  the  plasma  appears  to  be  utilized  in  the  nourish- 
ment of  the  parasite,  as  undissolved  red  cells  are  extruded  from  the 
anus.  (Leichtenstern.-)  The  number  of  worms  found  in  cadavers  varies 
greatly,  but  often  several  hundred  are  to  be  counted,  the  males  being 
one-third  as  numerous  as  the  females.  Leichtenstern^  counted  as  many 
as  3,000  in  a  fatal  case. 

Pathogenic  Action. — The  essential  action  of  the  parasite  in  the  causa- 
tion of  anemia  has  been  repeatedly  shown  by  the  prompt  recovery 
which  has  followed  its  expulsion.  Yet  the  anemia  has  progressed  in 
some  instances  after  the  expulsion  of  the  worm,  and  a  cure  cannot  be 
assured  in  the  very  advanced  stages  of  the  disease.  The  frequent 
losses  of  blood  are  undoubtedly  a  chief  cause  of  anemia,  since  the 
parasite,  though  small,  is  very  prodigal  of  the  blood,  and  the  severest 
cases  usually  show  most  parasites.  Yet  there  have  been  many  excep- 
tions to  this  rule,  and  some  fatal  cases  having  shown  very  few  parasites, 
like  that  of  Leichtenstern's  in  which  only  24  were  found,  it  has  been 
held  that  a  condition  of  specific  intestinal  intoxication  is  established  by 
the  growth  of  the  worms.  The  evidence  on  which  this  theory  is  based 
is,  however,  very  incomplete.  Lussana  found  that  the  urine  in  anchy- 
lostomiasis, when  injected  into  rabbits,  dissolves  red  cells  much  more 


420  MISCELLANEOUS  PARASITIC  DISEASES. 

actively  than  does  normal  urine,  and  Bohlaud  demonstrated  that  there 
is  a  very  active  destruction  of  albumens  in  this  form  of  anemia. 

Changes  in  the  Blood. — The  anemia  passes  more  or  less  rapidly 
through  milder  stages,  and  in  severe  cases  reaches  the  pernicious  grade. 

In  the  majority  of  instances  the  condition  observed  is  one  of 
chlorotic  anemia,  with  moderate  loss  of  red  cells  and  very  marked  loss  of 
Hb.  In  cases  with  over  4  million  red  cells  Zappert  found  50,  40,  and 
30  percent  of  Hb.  In  many  cases,  however,  the  changes  in  the  blood 
are  more  severe,  and  the  presence  of  megalocytes,  microcytes,  megalo- 
blasts,  and  increased  Hb -index,  renders  the  condition  identical  with 
cryptogenic  pernicious  anemia. 

In  the  progress  of  the  anemia  Leichtenstern,  distinguished  two  stages, 
which  can  be  most  clearly  traced  when  the  infection  is  very  active.  There 
is  an  initial  stage  of  acute  anemia,  when  the  parasites  are  actively  changing 
their  location  in  the  intestine,  which  is  marked  clinically  by  colicy  pains 
and  bloody  diarrhea.  Later  comes  the  stage  of  chronic  anemia,  maintained 
by  the  steady  consumption  of  blood  by  the  parasites  as  well  as  by  some 
intoxication. 

Leucocytosis  of  moderate  grade  is  frequently  observed,  especially 
during  the  early  stages.  Bucklers  found  20,000  white  cells  in  an  early 
case,  and  many  others  have  reported  intermediate  grades  of  leucocy- 
tosis. In  the  severe  grades  of  anemia  the  leucocytes  are  usually  di- 
minished, Zappert^  finding  only  1,800  in  one  instance.  The  eosino- 
phile  cells  are  nearly  always  in  excess  and  sometimes  reach  an  extreme 
proportion.  Tliis  fact  was  first  noted  by  Muller  and  Rieder,  and 
Zappert,^  but  a  very  higli  proportion  (53  perci?nt)  as  first  recorded 
by  Bucklers,  while  Leichtenstern  '  saw  cases  with  62  and  72  percent. 

BOTHRIOCEPHALUS    LATUS. 

This  tapeworm  measures  from  6-10  meters,  occasionally  12-16 
meters,  in  length,  and  is  distinguished  from  all  other  intestinal  para- 
sites by  the  combination  of  a  very  broad  segment  and  a  pigmented 
uterus  which  occupies  a  central  position  in  the  segment.  The  head 
has  neither  rostellum  nor  booklets.  The  eggs  are  oval,  .05  by  .035 
mm,  with  a  rather  thin  double  contoured  shell,  at  one  end  of  which  is 
a  cap,  while  the  undeveloped  embryo  is  found  to  consist  of  a  number 
of  large  yellowish  globules.  Infection  occurs  by  eating  uncooked  fish, 
which  is  the  intermediate  host.  This  practice  is  confined  largely  to 
the  French,  Swiss,  and  Italian  lakes,  the  shores  of  the  Baltic  and  North 
seas,  and  Japan,  but  owing  to  the  long  life  of  the  parasite,  infected  sub- 
jects have  been  encountered  in  many  other  countries.  The  writer  ob- 
tained four  adult  specimens  from  a  healthy  Swede  in  New  York  City, 
who  had  not  been  out  of  the  State  for  eleven  years. 

The  importance  of  this  parasite  in  the  etiology  of  pernicious  anemia 
was  demonstrated  by  Hoffmann,  Botkin,  Runeberg,  and  Schumann, 
and  its  mode  of  action  has  been  discussed  under  the  etiology  of  per- 
nicious anemia. 


FILARIASIS. 


421 


Fig.  30. 


FILARIASIS. 

Several  species  of  nematode  worms  inhabit  the  internal  vessels  and 
discharge  their  embryos  into  the  circulation,  giving  rise  to  the  condi- 
tion known  as  filariasis.  The  embryos  of  the  several  species  exhibit 
characters  which  should  render  possible  their  accurate  identification. 

According  to  Manson  these  features  are  principally  (1) 'Periodicity 
in  the  presence  of  the  embryos  in  the  peripheral  blood.  Filaria  diurna 
appears  during  the  day  and  disappears  at  night.  Filaria  nocturna  ap- 
pears at  night  only.  Filaria  pcrstans  and  Demarquaii  are  constantly 
present,  both  by  day  and  by  night.  (2)  The  presence  or  absence  of  a 
sheath  which  characterizes  all  species 
except  Filaria  perstans.  (3)  The  char- 
acter of  the  head  and  tail  ends ;  the 
presence  or  absence  of  an  armature ; 
the  blunt  or  pointed  shape  ;  the  length 
of  the  tapering  end.  (4)  Length, 
breadth,  and  general  appearance  of 
body.  (5)  Character  of  movements. 
Filaria  nocturna  and  diurna  are  lash- 
ing but  stationary.  Filaria  perstans, 
lashing  but  locomotor.  The  associated 
pathological  condition,  the  nativity  of 
the  patient,  and  the  character  and  loca- 
tion of  the  parent  worm,  if  found,  are 
also  important. 

Filaria  nocturna.  Developmental 
Cycle. — The  embryo  is  taken  up  from 
the  blood  of  the  host  by  the  mosquito, 
in  whose  stomach  it  becomes  rid  of  its 
sheath,  and  at  the  end  of  six  to  seven 
days  develops  in  the  viscera  of  the  in- 
sect to  a  length  of  1.58  mm.,  and  ac- 
quires four  lips  and  an  alimentary 
canal.  The  further  stages  between 
this  form  and  the  adult  filaria  of  Ban- 
croft have  not  been  traced.  The  worm 
is  next  found  in  the  lymphatics  of  the 

trunk  and  extremities,  where  it  was  first  seen  by  Bancroft  [F.  Ban- 
crofti).  Here  it  measures  70  (males)  to  94  mm.  (females)  in  length,  and 
looks  like  an  animated  white  thread.  Its  movements  are  active  and 
wriggling,  the  female  tending  to  coil.  The  young  filaria  are  discharged 
into  the  lymph,  and  traversing  the  nodes,  reach  the  blood  stream. 
The  reason  of  their  exclusive  appearance  during  the  night  is  not  known. 

Usually  the  presence  of  this  worm  and  its  embryos  leads  to  no  ap- 
preciable disturbance  in  the  body  of  the  host,  and  numerous  cases  have 
been  discovered  entirely  by  accident.  In  some  cases  chronic  inflam- 
mation of  the  lymphatics  results  in  a  variety  of  pathological  conditions, 


Filaria  nocturna  with  sheath.    (I,ewis.) 


422  MISCELLANEOUS  PARASITIC  DISEASES. 

principally  cliyluria,  lymphangitis,  lymph  scrotum,  etc.,  and  probably 
also  to  elephantiasis  Arabum. 

The  embryo  of  filaria  nocturna  is  a  slender,  snake-like  worm,  3  by 
.0075  mm.  in  dimensions,  with  sharp  pointed  tail  tapering  for  about 
one-fifth  the  length  of  the  body,  and  a  blunt  head.  The  head  is  com- 
posed of  a  six-lipped  prepuce  covering  an  extensive  proboscis  on  which 
is  a  protrusible  spine.  The  entire  worm  is  enclosed  in  a  delicate,  hya- 
line, transparent  sheath,  which  protrudes  beyond  head  or  tail,  and  within 
which  the  animal  moves.  This  sheath  exhibits  fine  cross-striations. 
The  movements  are  actively  lashing,  writhing,  coiling  and  uncoiling, 
but  u-ith  little  or  no  tendency  toward  locomotion.  The  movements  con- 
tinue for  several  hours,  or  until  the  blood  suffers  drying. 

Occurrence  in  the  Blood. — The  embryos  begin  to  make  their  appear- 
ance in  the  blood  from  five  to  seven  o'clock  in  the  evening.  The  exact 
hour  when  they  may  be  found  most  abundantly  is  much  affected  by 
the  habits  of  the  host.  The  numbers  increase  for  several  hours  during 
rest  in  bed,  and  after  midnight  they  usually  become  less  abundant,  dis- 
appearing at  seven  or  eight  in  the  morning,  but  an  occasional  speci- 
men may  sometimes  be  found  at  any  time  in  the  day.  This  remark- 
able periodicity  depends  on'  the  habits  of  the  host,  since  it  becomes 
transposed  when  the  subject  sleeps  in  the  daytime,  and  it  is  considerably 
disturbed  by  irregular  habits  and  by  fever.  It  is  also  adapted  to  the 
nocturnal  habits  of  the  mosquito.  The  numbers  of  filaria  to  be  found 
in  the  blood  depend  upon  the  time  of  the  examination  and  the  varia- 
tions in  the  number  of  parent  worms,  but  for  the  same  patients  they 
are  usually  quite  uniform.  From  10  to  50  may  be  found  under  one 
cover-glass  specimen,  but  they  are  often  much  less  abundant.  Several 
hours'  search  through  thick  blood  smears  may  be  required  for  the 
demonstration  of  a  single  filaria  embryo,  in  cases  in  which  they  are 
present  though  very  scarce.  It  is  sometimes  to  be  observed  tiiat  the 
results  of  the  blood  examination  are  negative  as  long  as  the  patient  is 
going  about,  although  a  moderate  number  of  embryos  are  found  after 
the  patient  has  been  in  bed  a  few  days.  Changes  in  the  blood  refer- 
able to  the  presence  of  filaria  embryos  are  not  usually  demonstrable. 
Even  when  present  in  enormous  numbers  and  for  many  years,  the 
parasites  exert  no  deleterious  action  on  the  red  or  white  cells,  and 
anemia,  when  present,  must  be  referable  to  secondary  causes. 

Method  of  Demonstration. — On  account  of  the  large  size  and  active 
movements  of  the  filaria,  examination  of  the  fresh  blood  may  be  rec- 
ommended in  the  search  for  the  parasite  when  its  presence  is  suspected. 
Fresh  specimens  prepared  in  rather  thick  layers  should  be  looked  over 
with  a  moderately  low  power  lens.  Permanent  specimens  may  be 
secured  by  smearing  the  blood  on  glass  slides,  fixing  by  heat  or  alcohol, 
and  staining  by  methylene-blue.  Canada  balsam  causes  fading  after  a 
year  or  more,  and  Manson  uses  glycerine-jelly  as  a  mounting  medium. 

Filaria  diurna. — In  four  cases  of  filariasis  occurring  in  negroes  on 
the  coast  of  Africa,  Manson  observed  filaria,  resembling^7aria  nocturna, 
in  the  blood  only  between  8  a.  m.  and  9  p.  m.     He  suggests  that  the 


BIBLIOGRAPHY.  423 

fllaria  loa  is  the  parent  form,  since  one  of  his  cases  had  previously 
suffered  from  this  parasite,  and  that  the  "  mangrove  fly  "  is  the  inter- 
mediate host. 

Fllaria  perstans. — In  some  portions  of  the  west  coast  of  Africa 
Mansou  found  that  two-thirds  of  the  natives  are  infected  with  a  spe- 
cial form  of  filaria.  The  embryos  are  thinner  and  longer  than  Fllaria 
nocturna,  23  by  .0045  mm.  ;  they  lack  a  sheath,  execute  movements, 
often  very  rapid,  of  locomotion,  occur  in  much  smaller  numbers  in  the 
blood,  and  are  found  both  by  day  and  by  night. 

BiBLIOGEAPHY. 

Miscellaneous  Parasitic  Diseases. 

Atkinson.     Philadelphia  Med.  Jour.,  Vol.  3,  p.  1243. 
Blumer,  Neuman.     Amer.  Jour.  Med.  Sci.,  Vol.  119,  p.  14. 
Bohland.     Munch,  med.  Woch.,  1894,  p.  901. 

Brmm.     Johns  Hopkins  Bull.,  1897.     Jour.  Exper.  Med.,  1898,  p.  315. 
Bucklers.     Munch,  med.  Woch.,  1894,  p.  22. 
Cabot.     Boston  Med.  Surg.  Jour.,  Vol.  137,  p.  676. 
Oinisella.     Annali  univ.  de  Med.,  1878. 

Demme.     Ber.,  Jenner  Kinderspital.  Bern.,  1890,  p.  31.     Cited  by  Grawitz. 
Orassi.     Archiv  p.  1.  sci.  Med.,  1879,  No.  20.     Annali  univ.  di  Med.,  1878. 
Griesinger.     Archiv  f.  phys.  Heilk.,  1854,  p.  554. 
Gwijn.     Cent.  f.  Bact.,  Bd.  25,  p.  746. 
Heisse.     Casper's  Vierteljahrschrift,  Bd.  8. 
Kartulis.     Virchow's  Archiv,  Bd.  152,  p.  471. 
Lambert,  Brooks.     Trans.  N.  Y.  Path.  Soc,  1900. 

Leichtenstern.     '  Wien.  klin.  Rundschau,  1898.     ^Deut.  med.  Woch.,  1887-88. 
Lortet,  ViaUeion.     Etude  s.  1.  Bilharz.  hematob.,  Paris,  1894. 
Lussana.     Eivista  clin.,  1890,  No.  4,  p.  750. 
Manson.     Allbutt's  Syst.  of  Med.,  Vol.  II. 
Menche.     Cent.  f.  klin.  Med.,  1882,  p.  161. 
Midler,  Bieder.     Deut.  Archiv  klin.  Med.,  Bd.  48,  p.  26. 

Perroncito.  Archiv  p.  1.  sci.  med.,  1881,  No.  2.  Compt.  Eend.  Acad.  Sci.,  1882, 
No.  1. 

V.  Schoff.     Wien.  med.  Zeitung,  1888,  Nos.  46^8. 

Sonderreger.     Correspond.,  Schweizer  Aerzte,  1880. 

Stump.     Philadelphia  Med.  Jour.,  Vol.  3,  p.  1318. 

Teissier.     Compt.  Rend.  Acad.  Sci.,  T.  121,  p.  171. 

Thayer.     Philadelphia  Med.  Jour.,  Vol.  1,  p.  654. 

Wucherer.     Deut.  Archiv  klin.  Med.,  1872. 

Zappert.     HVien.  klin.  Woch.,  1892,  No.  24.     ^Zeit.  f.  klin.  Med.,  Bd.  23. 

Zinn,  Jacohy.     Berl.  klin.  Woch.,  1896,  No.  36. 


ADDENDUM. 


JENNER'S    STAIN. 

Jenner's  method  of  fixing  and  staining  blood  has  now  withstood 
sufficient  trial  to  warrant  its  acceptance  as  one  of  the  most  important 
recent  methods  in  blood-technics.  The  specimens  are  fixed  and  stained 
in  the  same  solution,  which  is  prepared  as  follows  :  Equal  parts  of  1.2 
percent  to  1.25  percent  of  watery  solution  of  Griibler's  yellow  water- 
soluble  eosin,  and  of  1  percent  watery  solution  of  Griibler's  medicinal 
methylene-blue  are  mixed  together  in  an  open  basin,  thoroughly  stirred, 
and  allowed  to  stand  24  hours.  The  mixture  is  then  filtered,  dried 
in  the  air,  or  oven  at  55°  C,  the  filtrate  powdered,  shaken  up  with 
distilled  water,  and  washed  on  a  second  filter.  It  is  again  dried, 
powdered,  and  stored  in  bottles  for  use.  The  stain  is  prepared  by  dis- 
solving 0.5  gram  of  the  powder  in  100  cc.  pure  methyl  alcohol 
(Merck's  "  for  analytical  purposes"). 

Very  thin  smears  of  blood,  made  on  thoroughly  clean  slides,  are 
dried  in  the  air.  The  dye  is  poured  on  the  specimen,  and  staining  is 
complete  in  one  to  three  minutes.  The  specimens  are  washed,  pref- 
erably in  distilled  water,  till  of  a  pink  color,  which  usually  appears  in 
ten  seconds.  All  the  cells,  their  nuclei,  and  the  various  granules,  are 
well  differentiated,  while  the  malarial  parasite  is  densely  stained  and 
only  in  the  larger  parasites  does  the  chromatin  fail  to  appear  deeply 
red  stained.  For  this  last  purpose  the  method  is  inferior  to  Nocht's. 
(See  Lancet,  1899,  I.,  p.  370.)  The  powder  or  fluid  dye  may  be 
obtained  from  New  York  dealers. 


424 


INDEX. 


i  BSCESS,  284 
A     of  liver,  340 
Absorption,  effects  on  blood,  349 
Acetonemia,  71 
Acidemia  in  carcinoma,  373 
Acidity  of  blood,  79 
Actinomycosis,  291 
Addison's  disease,  325 
Albumens  of  serum,  62 
Albumose,  occurrence  in  blood,  65 
Alexines,  119 

Alkalescence  of  blood,  Engel's  alkalimeter, 
52 
estimation  of,  51 
Limbeck's  method,  53 
Lowy's  method,  52 
Schultz-Scbultzenstein'  s 

method,  53 
Wright's  method,  53 
in  carcinoma,  373 
in  cholera,  351 
in  diabetes,  324 
in  fever,  245 
general  factors  in,  77 
in  gout,  327 
in  hemoglobinemia,  319 
in  leukemia,  217 
in  uremia,  365 
Analyses  of  blood,  interpretation  of,  17 
Avchylostoma  duodenale,  418 

anemia  from,  177 
Anemia,  from  Bothriocephalus  latiis,  176 
changes  in  blood,  234 
infantum  pseudo-leukemica,  233 

pathological  anatomy,  234 
lymphatic,  146,  299 
progressive  pernicious,  172 

changes  in  blood  in,  187 
chemistry,  187 
Hb,  188 
leucocytes,  192 
red  cells,  189 
etiology,  general,  174 

special,  176 
gastro-intestinaldiseasesand, 

179 
hemorrhages  as  a  cause  of, 

_178_ 
historical,  172 
malaria  as  a  cause  of,  179 
marrow  lesions  in,  182 
nervous  system  in,  182 
pathogenesis  of,  186 
after  pregnancy,  178 
r^sum^  of  chief  facts,  193 


Anemia,  progressive,  scope  of  term,  175 
typhoid  fever  as  a  cause  of, 
179 
secondary,  eosins  in,  137 

origin  of,  101 
of  V.  Jaksch,  233 

significance  of,  235 
Anguillula  stercoralis,  418 
Anlaydrsemia,  17 
Anthrax,  291 
Anti-albumid,  61 
Antifebrine  poisoning,  316 
Antipyrine  poisoning,  316 
Antitoxine,  in  diphtheria,  efifects  on  blood, 

257 
Appendicitis,  283 
Arsenic,  effect  on  red  cells,  96 
Arseniuretted    hydrogen,    poisoning    by, 

315 
Ascaris,  417 
Ascites,  341 

Ash  of  blood,  inorganic  principles,  66 
Asphyxia,  355 
Asthma,  356 

eosinophilia  in,  356 

BACTERIA,  action  of,  on  blood,  245 
in  blood  of  pneumonia,  254 

in  cholera,  352 

in  chorea,  335 

in  endocarditis,  360 

in  influenza,  290 

in  leprosy,  305 

methods  of  examining  blood  for,  283 

in  purpura  hemorrhagica,  308 

in  rheumatism,  286 

in  scarlet  fever,  262 

in  scurvy,  312 

in  septic  processes,  282 

in  tuberculosis,  303 

in  typhoid  fever,  267 
Bactericidal  action  of  blood,  121 
Barlow's  disease,  313 
Basedow's  disease,  336 
Basic  capacity  of  blood,  79 
Basophilia,  perinuclear,  Neusser's,  114 
Baths,  cold,  in  typhoid  fever,  265 
Beri-beri,  335 
Bibliography,  carcinoma,  sarcoma,  375 

cliemistry,  79 

chlorosis,  171 

constitutional  diseases,  331 

development  of  blood  cells,  160 

diphtheria,  268 

eosinophilia,  148 


426 


INDEX. 


Bibliography,  exanthems,  268 

fever,  246 

general  physiology,  56 

heart,  366 

hemopoietic  system,  352 

hemorrhagic  diseases,  320 

infectious  diseases,  miscellaneous,  291 

V.  Jaksch  anaemia,  237 

kidneys,  366 

leprosy,  305 

leucocytes,  leucocytosis,  134 

leukemia,  220 

lungs,  366 

lymphocytosis,  148 

malaria,  409 

morphology  and  physiology,  103 

nervous  and  mental  diseases,  336 

parasitic  diseases,  423 

pernicious  anemia,  195 

pneumonia,  268 

pseudo-leukemia,  231 

relapsing  fever,  413 

splenectomy,  241 

syphilis,  305 

tuberculosis,  305 

tvphoid  fever,  268 

Widal's  test,  278 
Bile,  effects  of,  on  blood,  337 
Bilharzia  hematobia,  416 
Blackwater  fever,  317 
Blood-dust,  114 
Blood  plates,  chemistry  of,  62 
development  of,  159 
Blood-smears,  fixation  of,  44 
Bones,  tuberculosis  of,  302 
JBothriocephalus  latus,  420 

anemia  from,  176 
Breast,  carcinoma  of,  371 
Burns,  314 

flARBONIC  DIOXIDE,    occurrence  in 
\J        blood,  78 

Carbonic  oxide  Hb,  chemistry  of,  60 
spectrum  of,  25 
poisoning,  316 
Carcinoma,  368 

acidemia  in,  373 

alkalescence  in,  373 

of  esophagus,  342 

of  breast,  371 

of  liver,  339 

special  factors  in  anemia  of,  370 

specific  gravity  in,  372 

of  stomach,  346 

digestion  leucocytosis  in,  123 
Charcot-Leyden  crystals  in  leukemia,  217 
Chemistry  of  blood,  59 

in  diabetes,  323 

in  gout,  326 

in  leukemia,  217 

in  myxedema,  331 

in  nephritis,  363 

in  osteomalacia,  327 

in  pernicious  anemia,  187 

in  pneumonia,  249 

in  rachitis,  330 


Chemistry   of  blood,  in  septic  processes, 
281 

in  tuberculosis,  302 

in  uremia,  365 
Chemotaxis,  116 
Children,  blood  in  vaccinia,  260 

digestion  leucocytosis  in,  124 

eosins  in  blood  of,  137 

gastro-intestinal  diseases  of,  344 

syphilis  in,  297 
Chlorosis,  163 

chemistry  of,  167 

eosins  in,  137 

etiologv,  163 

Hb,  165 

iron  in,  163,  168-170 

leucocytes,  169 

marrow  in,  165 

nervous  system  in,  164 

nucleated  red  cells,  167 

pseudo-,  170 

red  cells  of,  166 

regeneration  of  blood,  168 

specific  gravity,  165 

thyroid,  336 

varieties  of,  169 
Cholelithiasis,  340 

Cholemia,  occurrence  and  detection  of,  72 
Cholera,  350 

alkalescence  in,  351 

bacteria  in,  352 

infantum,  lymphocytosis  of,  344 
Chorea,  335 

bacteria  in,  335 
Chromic  acid  poisoning,  316 
Cirrhosis  of  liver,  340,  341 
Coagulability,  determination  of,  53 

in  hemoglobinemia,  319 
Coagulation,  in  blood  of  fever,  244 
Cold,  effect  in  concentrating  blood,  19 
Colitis,  350 

Concentration  of  blood,  effect  of  cold  on,  19 
of  electricity  on,  19 
of  massage  on,  19 
Conjugation  of  malarial  parasites,  400 
Constitutio  lymphatica,  in  leukemia,  202 
Constitutional  diseases,  322 
Convulsions,  334 

DEFIBRINATED  blood,  transfusion  of, 
315 
Depletion,  effects  of,  on  blood,  349 
Dementia,  333 

Development  of  blood  cells,  149 
Diabetes,  322 

alkalescence  in,  324 

Bremer's  reaction  in  blood  of,  54 

chemistry  of,  323 

glycogen  in,  324 

jecorin  in,  324 
Diarrhea,  350 

Diarrheal  diseases,  polycythemia  of,  93 
Diastatic  ferment,  71 
Digestion,  effect  on  red  cells,  90 

leucocytosis,  123,  348 
Diphtheria,  255 


INDEX. 


427 


Diphtheria,    antitoxin   in,    effects   of,   on 
blood,  257 

degeneration  of  leucoc}i;es  in,  257 

lymphocytosis  in,  257 
Distoma  hematobium,  416 
Dry  specimens,  46 
Duodenal  ulcer,  349 
Dysentery,  350 
Dyspepsia,  343 

ECHINOCOCCUS,  in  liver,  341 
Electricity,    effect   in    concentrating 
blood,  19 
Emphysema,  356 

Empyema,   complicating  pneumonia,  252 
Endocarditis,  357 

bacteria  in,  360 

malignant,  359 

polycythemia  of,  94 
Eosinophilia,  137 

in  anchylostomiasis,  420 

with  ascarides,  etc.,  418 

in  asthma,  356 

in  diagnosis,  142 

in  leukemia,  213 

marrow-changes  in,  141 

origin  and  significance,  141 

in  pneumonia,  252 

post-febrile,  139 

in  rachitis,  327 

relation  to  lymphocytosis,  147 

in  sarcoma,  374 

in  scarlet  fever,  262 

in  trichinosis,  415 
Eosinophile  cells,  chemistry  of,  159 

development  of,  158 

estimation  of,  38 

proportions.  111 
Epilepsy,  333 

lymphocytosis  in,  334 
Erysipelas,  285 
Esophagus,  lesions  of,  342 
Exanthemata,  259 

eosins  in,  139 

I  .''AT,  demonstration  of,  56 
occurrence  and  estimation  of,  71 
Ferment,  glycolytic,  324 
Ferrometer,  Jolles',  45 
Fever,  alkalescence  in,  245 

blood  in,  243 

hemocytolysis  in,  243 
Filariasis,  421 

Fixation  of  blood-smears,  47 
Flagellate  bodies,  preparation  of,  378 
Fleischl'  s  hemoglobinometer,  39 

GASTRITIS,  343 
Gastro-intestinal  diseases,  and  perni- 
cious anemia,  179 
Glanders,  291 

Glucose,  occurrence  and  estimation  of,  69 
Glycogen  demonstration  of,  55 
in  diabetes,  324 
in  leukemia,  217 
occurrence,  69 


Glycogen  in  pneumonia,  253 
Glycolytic  ferment,  324 
Granules,  Ehrlich's,  108,  110 
Gonorrhea,  288 

eosins  in,  140 
Gout,  326 

alkalescence  in,  327 

chemistry  of,  326 

eosins  in,  140 

uric  acid  in  blood  of,  326 
Gower's  hemoglobinometer,  39 
Graves'  disease,  336 
Guiacol,  poisoning  by,  315 

HB,  hemoglobin,  24 
chemistry  of,  59 
spectrum  of,  24 
Heart,  congenital  disease  of,  361 

diseases  of,  357 
Hemameba  immaculata,  395,  390 
Hematin,  chemistry  of,  61 

spectrum  of,  25 
Hematocrit,  26 
Hematocytometer,  30 

Oliver's,  35 

Thoma's,  30 

directions  for  using,  32 
sources  of  error,  34 
Hematoidin,  chemistry  of,  61 

in  globulicidal  serum,  64 
Hemocytolosis,  314 

in  fever,  243 
Hemoglobinemia,  60 

alkalescence  in,  319 

coagulability  in,  319 

malarial,  317 
Hemoglobinometer,  38 

Fleischl' s,  39 

Gower's,  39 

Miescher's,  41 

Oliver's,  43 
Hemoglobinuria,  317 
Hemokonia,  114 
Hemophilia,  310 

Hemorrhage,   a  cause  of  pernicious  ane- 
mia, 178 
Hemorrhage,  changes  in  blood  from,  98 
Hemorrhagic  diseases,  307 
Hemosiderin,  chemistry  of,  61 
Histon,  chemistry  of,  62 
Hydremia,  febrile,  244 
Hydrobilirubin,  67 
Hydrocyanic  acid  poisoning,  316 
Hyperacidity,  gastric,  343 
Hypochondriasis,  335 
Hypoleucocytosis,  experimental,  118 

in  pneumonia,  252 
Hysteria,  335 

INFLUENZA,  289 

L        bacteria  in,  290 

Inorganic  principles  of  blood,  estimation 

of,  67 
Interpretation  of  analyses  of  blood,  17 
Intestinal  intoxication  in  leukemia,  201 
Intestine,  diseases  of,  349 


428 


INDEX. 


Iron  in  blood,  estimation  of,  45 
in  chlorosis,  163,  168,  169,  170 
effect  of,  on  red  cells,  94 
indications  for,  95 
occurrence  of,  67 

V.   TAKSCH,  anemia,  relation  to  pseudo- 

V     leukemia,  224 
Jaundice,  338 

polycythemia  in,  339 
Jecorin,  in  diabetes,  324 
Jenner's  stain,  424 
Jolles'  ferrometer,  46 
Justus'  test,  295 

TAIDNEY,  diseases  of,  361 

T  EAD,  effects  on  blood,  97 
L     Leprosy,  304 

bacteria  in,  305 

serum  diagnosis  of,  305 
Leucocytes,  acute  degeneration,  113 
chemistry  of,  01 
chronic  degeneration,  113 
classification,  108 
degeneration  of,  in  diphtheria,  257 

in  pneumonia,  253 
degenerative  changes  in,  112,  212-214 
development  of,  154 

of  varieties,  157 
diminution  of  neutrophile  granules, 

113 
estimation  of,  36 

in    same    preparation   witli    red 
cells,  36 _ 
fatty  degeneration,  114 
finer  structure,  109 
fragmentation  of  bodies,  113 
hydropic  degeneration,  114 
morphology,  106 
neutrophile,  development  of,  157 
nuclear  clianges,  113 
numbers,  110 
in  pathological  blood,  107 
pigmented,  in  malaria,  408 
polynuclear,  degenerative  changes  in, 

213 
proportions  of  forms.  111 
Leucocytosis,  ante-mortem,  130 

in  leukemia,  216 
cachectic,  128 

changes  in  marrow,  117,  119 
classification,  115 
clinical  types,  122 
course  of,  118 
digestion,  348,  123 
experimental,  131 
in  malaria,  407 
in  new-born  infants,  126 
in  phthisis,  301 
post-hemorrhagic,  99,  127 
in  pregnancy,  125 
relation  to  immunity,  119 
significance  of  inflammatory,  115 
Leukemia,  198 


Leukemia,  alkalescence  in,  217 

changes  in  blood,  210 
leucocytes,  211 
red  cells,  210 
in  viscera,  204 

Charcot-Leyden  crystals  in,  217 

chemistry,  217 

diagnosis,  219 

eosins  in,  137,  213 

etiology,  201 

extirpation  of  spleen  in,  240 

glycogen  in,  217 

history,  198 

intestinal  intoxication  in,  201 

leucocytosis,  ante-mortem,  in,  216 

lymphatic,  215 

lymphocytes  in,  214 

malaria  as  a  cause  of,  202 

marrow  in,  204 

mast-cells  in,  215 

nucleins  in,  218 

pathogenesis,  208 

peptone  in,  217 

protozoa  in,  203 

rachitis  as  a  cause  of,  202 

relation  to  pseudo-leukemia,  226 

resemblance  to  a  neoplasm,  209 

septicemia  in,  216 

specific  gravity  in,  217 

spermin  in,  216 

stomatitis  as  a  cause  of,  202 

syphilis  as  a  cause  of,  202 

transformation   into  pernicious   ane- 
mia, 217 

transformations  of  type,  217 

tuberculin  in,  216 

types  of  myelocytes  in,  211 

tyrosin  in,  217 

uric  acid  in,  218 

variations  in  blood  changes,  216 

xanthin  bodies  in,  218 
Lipacidemia,  71 
Liver,  337 

abscess  of,  340 

acute  yellow  atrophy  of,  341 

cancer  of,  339 

diseases  of,  eosins  in,  138,  337 

echinococcus  cyst  of,  341 

embryonal,  nucleated  red  cells  in,  153 

hypertrophic  cirrhosis,  340 
Lungs,  diseases  of,  354 
asphyxia,  355 
bronchitis,  357 
emphysema,  356 
eosins  in,  137,  356 
Lutein,  67 

Lymphatic  leukemia,  transformation  into 
myelemia,  205 
marrow  in,  204 
Lymphocytes,  development  of,  157 

large,  in  pneumonia,  252 

in  leukemia,  214 

degenerative  changes  in,  214 
large,  214 

peculiar,  in  pneumonia,  253 

proportions,  111 


INDEX. 


429 


Lymphocytes    relation      to     neutrophile 

cells,  209 
Lymphocytosis  in  cholera  infantum,  344 

in  congenital  syphilis,  297 

in  diphtheria,  257 

in  epilepsy,  334 

experimental,  147 

large  cells  in,  147 

in  malaria,  407 

occurrence  of,  144 

origin  of,  147 

in  rachitis,  329 

relation  to  eosinophilia,  147 

in  sarcoma,  374 

in  typhoid  fever,  266 
Lymphoma,  224 
Lymphosarcoma  in  pseudo-leukemia,  225 

MALAEIA,  377 
anemia  of,  404 

pathogenesis  of,  406 
a  cause  of  leukemia,  202 

pernicious  anemia,  179 
chronic,  403 
coma  in,  402 
conjugation,  400 
crescentic  bodies,  396 
development  of  parasite  in  mosquito, 

399 
without  diminution  of  red  cells,  403 
eosins  in,  139 

estivo-autumnal  parasite,  389 
extirpation  of  spleen  in,  240 
flagellate  bodies,  397 
hemamehn  immaculata,  390,  395 
hemoglobinemia,   31 7 
leucocytosis  of,  407 
lymphocytosis  in,  407 
nucleus  and  chromatin  of  parasites, 

384,  385,  386,  392 
occurrence  of  parasites  in  blood,  401 
without  parasites  in  blood,  402 
pliagocytosis  in,  408 
pigment,  estivo-autumnal,  392,  396 
pigmented  leucocytes,  408 
quartan  parasite,  388 
quotidian  parasite,  398 
red  cells  in,  405 
remittent,  403 

rings,  comparison  of  tertian  and  es- 
tivo-autumnal, 333 

estivo-autumnal  signet,  389 

significance  of,  382 

tertian,  381 
rosettes,  estivo-autumnal,  391 

quartan,  389 

tertian,  387 
species,  plurality  of,  392 
technics,  377 
tertian  parasite,  381 
typhoid  fever  and,  403 
Malta  fever,  290 

serum  diagnosis  of,  291 
Mania,  333 

Marrow,  extrusion  of  nuclei  of  red  cells 
in,  152 


Marrow,  giant  cells  fn,  156 
in  chlorosis,  165 

lesions  in  pernicious  anemia,  182,  183 

in  leukemia,  204 

in  lymphemia,  205 

malarial  parasites  in,  397 

normal  limits  of  red,  153 
Massage,    effect   in    concentrating  blood, 

19 
Mast-cells,  development  of,  157 

in  leukemia,  215 

occurrence  of,  142 

proportions.  111 

staining  of,  49 
Measles,  262 

German,  263 

protozoa  in,  263 
Megaloblasts,  structure,  significance,  85 
Megalocytes,  occurrence,   significance,  84 
Melancholia,  333 
Melanin,  chemistry  of,  61 
Melena  neonatorum,  syphilitic,  297 
Meningitis,  tuberculous,  302 
Menstruation,  red  cells  in,  90 
Mental  diseases,  333 
Mercury,  effects  on  blood  in  sj'philis,  294 

on  red  cells,  96 
Methemoglobin,  chemistry  of,  60 

spectrum  of,  25 
Methemoglobinemia,  316 
Microcytes,  occurrence,  significance,  83 
Miescher's  hemoglobinometer,  41 
Mosquito,  development  of  malarial  para- 
site in,  399 
Mucinemia  in  myxedema,  331 
Myelocytes  in  congenital  syphilis,  297 

degenerative  changes  in,  212,  213 

morphology,    107,  211 

occurrence  of,  143 

in  pneumonia,  253 

types  of,  in  leukemia,  211 
Myxedema,  330 

chemistry  of,  331 

mucinemia  in,  331 

thyroid  therapy  in,  330 


NEPHRITIS,  362 
chemistry  of  blood  in,  363 
eosins  in,  138 
Nervous  diseases,  333 

eosins  in,  138,  333 
influences,    effect    on  quality  of 
blood, 18 
system  in  chlorosis,  164 

in  pernicious  anemia,  182 
Neurasthenia,  335 
Nitrites,  poisoning  by,  315 
Nitrobenzol  poisoning,  315 
Nocht-Romanowsky  method,  370 
Normoblasts,  occurrence,  significance,   84 
Nucleated  red  cells,  84 

transformation  into  discs,  152 
Nuclein,  chemistry  of,  62 
Nucleins  in  leukemia,  218 
Numbers  of  blood  cells,  30 


430 


INDEX. 


OBESITY,  324 
Oligocythemia,  97 
Oligoplasmia  in  cholera,  351 
Oliver's  hemoglobinometer,  43 
Osmotic  relations  of  blood,  75 

tension,  estimation  of,  53 
Osteomalacia,  327 

chemistry  of,  327 

eosins  in,  140 
Osteomyelitis,  280 
Osteosarcoma,  374 
Oxyhemoglobin,  chemistry  of,  60 
Oxyuris,  417 

PAEASITES,  intestinal,  eosins  in,  140 
Paresis,  333 
Peptone,  in  leukemia,  217 

occurrence  in  blood,  65 
Pericarditis,  287 
Peritonitis,  287 

Pernicious  anemia,  changes  in  blood,  187 
in  chemistry,  187 
inHb,  188' 
in  leucocytes,  192 
in  red  cells,  189 
lesions  in  marrow,  183 
"microcytic,"  309 
pathogenesis,  186 
progressive,  172 

etiology  of,  general,  174 

special,  176 
historical,  l72 
scope  of  term,  175 
relation  to  pseudo-leukemia,  227 
Resume  of  chief  facts,  193 
transformation  into  leukemia,  202 
Phagocytosis  in  malaria,  408 

relation  to  immunity,  119 
Phthisis,  leucocvtosis  in,  301 
Plague,  290 

serum  diagnosis  of,  290 
Plethora,  17,  91 
Pleurisy,  287 
Pneumonia,  248 

blood  of,  bacteria  in,  254 
degeneration  of  leucocytes  in,  253 
eosinophilia  in,  252 
glycogen  in,  253 
hypo-leucocytosis  in,  252 
lymphocytes,  large,  in,  252 

peculiar  in,  253 
myelocytes  in,  253 
toxicity  of  serum  in,  249  * 

Poikilocytosis,  86 
Poisoning  b}'  antifebrine,  316 
by  antypyrine,  316 
by  arseniuretted  hydrogen,  315 
by  carbonic  oxide,  316 
by  chromic  acid,  316 
by  guiacol,  315 
by  hydrocyanic  acid,  316 
illuminating  gas,  polycythemia  of,  94 
by  nitrites,  315 
by  nitrobenzol,  315 
by  phosphorus,  polycythemia  of,  94 
by  potassium  chlorate,  316 


Poisoning  by  pyrogallol,  316 

by  toadstools,  315 
Polychromasia,  86 
Polycythemia,  91 

after  cold  baths,  94 

of  diarrheal  diseases,  93 

of  endocarditis,  venous  stasis,  etc.,  94 

of  high  altitudes,  92 

of  illuminating  gas  poisoning,  94 

in  jaundice,  339 

of  ne^v-born  infants,  92 

of  phosphorus  poisoning,  94 
Potassium  chlorate  poisoning,  316 
Pregnancy,  leucocytosis  of,  125 

pernicious  anemia  after,  178 

red  cells  in,  91 
Protozoa,  in  leukemia,  203 

in  measles,  263 

in  variola,  260 
Pseudo-leukemia,  223 

acute,  226 

anatomical  lesions  of,  224 

changes  in  blood  of,  229 

diagnosis  of,   230 

history,  223 

infectious  origin  of,  228 

lymphosarcoma  in,  225 

relation  of,  to  leukemia,  226 
to  pernicious  anemia,  227 
to  tuberculosis,  227 

sarcoma  of  spleen  in,  231 

skin  in,  224 

syphilis  of  spleen  in,  231 
Psychical  emotions,  effect   on  quality  of 

blood,  19 
Purges,  effect  of,  on  blood,  349 
Purpura  hemorrhagica,  307 
bacteria  in,  308 
non-infectious,  idiopathic,  309 
Pyemia,  280 
Pyrogallal  poisoning,  316 

QUALITY  of  blood,  effect  of  nervous  in- 
fluences on,  18 
Quantity  of  blood,  26 

RACHITIS,  328 
as  cause  of  leukemia,  202 

chemistry  of,  330 

eosinophilia  in,  327 

hyperplasia  of  spleen  in,  329 

lymphocytosis  in,  327 
Red  cells,  chemical  composition,  59 

development  of,  149 

granular  degeneration,  88 

influence    of    therapeutic    measures 
upon,  94 

morphology  and  physiology,  82 

numbers  of,  89 

pathological  changes  in,  85 

size  of,  83 

staining  reactions,  82 
Reduced  Hb,  chemistry  of,  60 
Relapsing  fever,  411 

serum  diagnosis  in,  413 
Resistance  of  red  cells  in  fever,  244 


INDEX. 


431 


Kespiration,  effects  on  blood,  354 
Kheumatism,  285 

bacteria  in,  286 

eosins  in,  139 

SALT  solution,  infusion  of,  315 
Sarcoma,  373 

eosinophilia  in,  374 
lymphocytosis  in,  374 
of  spleen  in  pseudo-leukemia, 231 
Scarlet  fever,  261 

eosins  in,  139 
bacteria  in,  262 
eosinophilia  in,  262 
Scurvy,  311 

bacteria  in,  312 
Septicemia,  280 

in  leukemia,  216 
Serum,  albumens  of,  62 
chemistry  of,  62 
globulicidal  action  of,  64 
infusion  of,  315 
inorganic  principles  of,  63 
specific  gravity  of,  63 
Serum-diagnosis  in  leprosy,  305 
of  malta  fever,  291 
of  plague,  290 
in  relapsing  fever,  413 
of  typhoid  fever,  271 
Sex,  influence  on  numbers  of  red  cells,  90 
Skin  diseases,  eosins  in,  139 
in  pseudo-leukemia,  224 
Smears  of  blood,  method  of  preparing,  47 
Snake-poison,  315 
Specific  gravity,  in  carcinoma,  372 
estimation  of,  49 

Hammarschlag's  method,  49 
Schmaltz' s  method,  51 
general  variations  of,  73 
in  leukemia,  217 
of  serum,  63 
Spectra  of  blood  pigments,  25 
Spectrophotometer,  Glan's,  325 
Spermin  in  leukemia,  216 
Spindle  cells,  159 
Spirillum  of  Obermeier,  411 
Spleen,  aspiration  of,  in  typhoid  fever,  267 
epithelinme  primitive  of,  231 
extirpation  of,  in  leukemia,  240 

in  malaria,  240 
hyperplasia  of,  in  rachitis,  329 
sarcoma  of,  in  pseudo-leukemia,  231 
syphilis  of,  in  pseudo-leukemia,  231 
Splenectomy,  238 
in  animals,  238 
in  man,  239 
Staining  methods,  48 

dahlia,  for  mast-cells,  49 
eosin,  methylene-blue,  48 
Jenner's,  424 
triacid  mixture,  49 
Nocht's,  370 
Stomach,  carcinoma  of,  346 
digestion  leucocytosis,  123 
dilatation  of,  344 
diseases  of,  343 


Stomach,  ulcer  of,  345 
Stomatitis,  a  cause  of  leukemia,  202 
Suppuration,  281 
Syphilis,  293 

a  cause  of  leukemia,  202 

congenital,  297 

lymphocytosis  in,  297 
myelocytes  in,  297 

eosins  in,  l40 

of  spleen  in  pseudo-leukemia,  231 

TECHNICS,  23 
in  malaria,  377 
Tenia,  417 

Tests  for  blood,  qualitative,  23 
guiacum,  23 
spectroscopic,  24 
Teichmann's,  hemin,  24 
Tetanus,  290 
Tetany,  335 

Thoma's  hematocytometer,  30 
Thyroid  chlorosis,  336 

therapy  in  myxedema,  330 
Toadstools,  poisoning  by,  315 
Tonsillitis,  287 

Toxicity  of  serum,  in  pneumonia,  249 
Transfusion,  effects  of,  100,  315 
Trichinosis,  415 
Tuberculin  in  leukemia,  216 
Tuberculosis,  298 
bacteria  in,  303 
of  bones,  302 
chemistry  of,  302 
meningitis,  302 

relation  to  pseudo-leukemia,  227 
Tumors,  eosins  in  blood,  138,  368,  374 
Typhoid  fever,  264 

aspiration  of  spleen  in,  267 

bacteria  in,  267 

bilious,  413 

a  cause   of    pernicious   anemia, 

179 
cold  baths  in,  265 
lymphocytosis  in,  266 
serum  diagnosis  of,  271 
Typhus  fever,  289 
Tyrosin  in  leukemia,  217 

UKEA,  occurrence  and  estimation  of,  68 
Uremia,  365 

alkalescence  in,  365 
chemistry  of,  365 
Uric  acid,  in  blood  of  gout,  326 
in  leukemia,  218 
occurrence  and  estimation  of,  68 
"tlireadtest,"  326 

YACCINIA,  260 
V  blood  in,  in  children,  260 

Varicella,  260 
Variola,  259 

protozoa  in,  260 
Varioloid,  259 
Vermiculus,  of  malaria,  398 
Volume  of  red  cells  and  plasma,  36 


432 


INDEX. 


WANDERING  cells,  primary,  154 
Werlhoff's  disease,  307 
Whole  blood,  chemistry  of,  64 

quantitative  estimation  of  albu- 
mens of,  65 
Whooping-cough,  287 
Widal's  test,  271 


VANTHIN  bodies  in  leukemia,  218 
YELLOW  fever,  288 


yAPPERT  chamber,  37 


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